Inhibitors of prenyl-protein transferase

ABSTRACT

The present invention is directed to peptidomimetic macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.

RELATED APPLICATION

[0001] The present patent application is a continuation-in-partapplication of copending provisional application Ser. No. 60/175,801,filed Jan. 12, 2000.

BACKGROUND OF THE INVENTION

[0002] The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are partof a signalling pathway that links cell surface growth factor receptorsto nuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

[0003] Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a “CAAX” or “Cys-Aaa¹-Aaa²-Xaa” box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The term prenyl-protein transferase may be used to generallyrefer to farnesyl-protein transferase and geranylgeranyl-proteintransferase. The Ras protein is one of several proteins that are knownto undergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

[0004] Inhibition of farnesyl-protein transferase has been shown toblock the growth of Ras-transformed cells in soft agar and to modifyother aspects of their transformed phenotype. It has also beendemonstrated that certain inhibitors of farnesyl-protein transferaseselectively block the processing of the Ras oncoprotein intracellularly(N. E. Kohl et al., Science, 260:1934-1937 (1993) and G. L. James etal., Science, 260:1937-1942 (1993). Recently, it has been shown that aninhibitor of farnesyl-protein transferase blocks the growth ofras-dependent tumors in nude mice (N. E. Kohl et al., Proc. Natl. Acad.Sci U.S.A., 91:9141-9145 (1994) and induces regression of mammary andsalivary carcinomas in ras transgenic mice (N. E. Kohl et al., NatureMedicine, 1:792-797 (1995).

[0005] Indirect inhibition of farnesyl-protein transferase in vivo hasbeen demonstrated with lovastatin (Merck & Co., Rahway, N.J.) andcompactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al.,Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

[0006] Inhibitors of farnesyl-protein transferase (FPTase) have beendescribed in two general classes. The first are analogs of farnesyldiphosphate (FPP), while the second class of inhibitors is related tothe protein substrates (e.g., Ras) for the enzyme. The peptide derivedinhibitors that have been described are generally cysteine containingmolecules that are related to the CAAX motif that is the signal forprotein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reisset al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for thefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)). In general, deletion of the thiol from a CAAX derivativehas been shown to dramatically reduce the inhibitory potency of thecompound. However, the thiol group potentially places limitations on thetherapeutic application of FPTase inhibitors with respect topharmacokinetics, pharmacodynamics and toxicity. Therefore, a functionalreplacement for the thiol is desirable.

[0007] It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

[0008] It has recently been disclosed that certain tricyclic compoundswhich optionally incorporate a piperidine moiety are inhibitors ofFPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containinginhibitors of farnesyl protein transferase have also been disclosed (WO95/09001 and EP 0 675 112 A1).

[0009] It is, therefore, an object of this invention to developpeptidomimetic compounds that do not have a thiol moiety, and that willinhibit prenyl-protein transferase and thus, the post-translationalprenylation of proteins. It is a further object of this invention todevelop chemotherapeutic compositions containing the compounds of thisinvention and methods for producing the compounds of this invention.

SUMMARY OF THE INVENTION

[0010] The present invention comprises peptidomimetic macrocycliccompounds which inhibit the prenyl-protein transferase. Furthercontained in this invention are chemotherapeutic compositions containingthese prenyl-protein transferase inhibitors and methods for theirproduction.

[0011] The compounds of this invention are illustrated by the formula A:

DETAILED DESCRIPTION OF THE INVENTION

[0012] The compounds of this invention are useful in the inhibition ofprenyl-protein transferase and the prenylation of the oncogene proteinRas. In a first embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula A:

[0013] wherein:

[0014] R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are independentlyselected from:

[0015] a) hydrogen,

[0016] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,(R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,

[0017] c) unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆ alkynyl,wherein the substituent on the substituted C₁-C₆ alkyl, substitutedC₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected fromunsubstituted or substituted aryl, heterocyclic, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, halogen, R¹⁰O—,R⁴S(O)_(m)—, R⁴S(O)₂NR¹⁰—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—;

[0018] or two R^(1a)s, two R^(1b)s, two R^(1c)s or two R^(1e)s, on thesame carbon atom may be combined to form —(CH₂)_(v)—, wherein one of theCH₂ moieties is optionally replaced with —C(═O)—, —NH— or —NHC(═O)—;

[0019] R⁴ is selected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle,aryl, unsubstituted or substituted with:

[0020] a) C₁₋₄ alkoxy,

[0021] b) aryl or heterocycle,

[0022] c) halogen,

[0023] d) HO,

[0024] e)

[0025] f) —SO₂R¹¹

[0026] g) N(R¹⁰)₂, or

[0027] h) C₁₋₄perfluoroalkyl;

[0028] R⁶ and R⁷ are independently selected from:

[0029] 1) hydrogen,

[0030] 2) R¹⁰C(O)—, or R¹⁰OC(O)—, and

[0031] 3) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-6 cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with one or more substituents selectedfrom:

[0032] a) R¹⁰O—,

[0033] b) aryl or heterocycle,

[0034] c) halogen,

[0035] d) R¹⁰C(O)NR¹⁰—,

[0036] e)

[0037] f) —SO₂R¹¹

[0038] g) N(R¹⁰)₂,

[0039] h) C₃₋₆ cycloalkyl,

[0040] i) C₁-C₆ perfluoroalkyl,

[0041] j) (R¹⁰)₂N—C(NR¹⁰)—,

[0042] k) R¹⁰OC(O)—,

[0043] l) R¹¹OC(O)NR¹⁰—,

[0044] m) CN, and

[0045] n) NO₂, or

[0046] R⁶ and R⁷ may be joined in a ring;

[0047] R⁸ is independently selected from:

[0048] a) hydrogen,

[0049] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹²O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0050] c) C₁-C₆ alkyl unsubstituted or substituted by unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl,Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NH—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,R¹¹C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹⁰OC(O)NH—;

[0051] R⁹ is selected from:

[0052] a) hydrogen,

[0053] b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br,R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,NO₂, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0054] c) C₁-C₆ alkyl unsubstituted or substituted by C₁-C₆perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—;

[0055] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl,unsubstituted or substituted benzyl, unsubstituted or substituted aryland unsubstituted or substituted heterocycle;

[0056] R¹¹ is independently selected from C₁-C₆ alkyl unsubstituted orsubstituted aryl and unsubstituted or substituted heterocycle;

[0057] R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₃perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, and C₁-C₆alkyl substituted with unsubstituted or substituted aryl orunsubstituted or substituted heterocycle;

[0058] A¹ is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);

[0059] A² is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—, —NR¹⁰C(O)NR¹⁰—, S(O)_(m) and—C(R^(1c))₂—;

[0060] W is heteroaryl;

[0061] V is selected from:

[0062] a) heteroaryl, and

[0063] b) aryl;

[0064] X is selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)—O—,—O—C(O)NR¹⁰—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—and S(O)_(m);

[0065] Z¹ is selected from unsubstituted or substituted aryl andunsubstituted or substituted heterocycle, wherein the substituted arylor substituted heterocycle is substituted with one or more of:

[0066] 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0067] a) C₁₋₄ alkoxy,

[0068] b) NR⁶R⁷,

[0069] c) C₃₋₆ cycloalkyl,

[0070] d) aryl or heterocycle,

[0071] e) HO,

[0072] f) —S(O)_(m)R⁴,

[0073] g) —C(O)NR⁶R⁷, or

[0074] h) C₁₋₄ perfluoroalkyl;

[0075] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0076] 3) halogen,

[0077] 4) OR⁶,

[0078] 5) NR⁶R⁷,

[0079] 6) CN,

[0080] 7) NO₂,

[0081] 8) CF₃,

[0082] 9) —S(O)_(m)R⁴,

[0083] 10) —OS(O)₂R⁴,

[0084] 11) —C(O)NR⁶R⁷,

[0085] 12) —C(O)OR⁶, or

[0086] 13) C₃-C₆ cycloalkyl;

[0087] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0088] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0089] 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0090] a) C₁₋₄ alkoxy,

[0091] b) NR⁶R⁷,

[0092] c) C₃-6 cycloalkyl,

[0093] d) aryl or heterocycle,

[0094] e) HO,

[0095] f) —S(O)_(m)R⁴,

[0096] g) —C(O)NR⁶R⁷, or

[0097] h) C₁₋₄perfluoroalkyl;

[0098] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0099] 3) halogen,

[0100] 4) OR⁶,

[0101] 5) NR⁶R⁷,

[0102] 6) CN,

[0103] 7) NO₂,

[0104] 8) CF₃,

[0105] 9) —S(O)_(m)R⁴,

[0106] 10) —OS(O)₂R⁴,

[0107] 11) —C(O)NR⁶R⁷,

[0108] 12) —C(O)OR⁶, or

[0109] 13) C₃-C₆ cycloalkyl;

[0110] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0111] m is0, 1 or 2;

[0112] n is 0, 1, 2, 3 or 4;

[0113] p is 0, 1, 2, 3 or 4;

[0114] q is 1 or 2;

[0115] r is 0 to 5;

[0116] s is independently 0, 1, 2 or 3;

[0117] t is 1, 2, 3, 4, 5, 6 or 7; and

[0118] v is 2 to 6;

[0119] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0120] In a second embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula A:

[0121] wherein:

[0122] R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are independentlyselected from:

[0123] a) hydrogen,

[0124] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,(R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,

[0125] c) unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆ alkynyl,wherein the substituent on the substituted C₁-C₆ alkyl, substitutedC₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected fromunsubstituted or substituted aryl, heterocyclic, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(O)—, CN, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, andR¹¹OC(O)—NR¹⁰—;

[0126] or two R^(1e)s, on the same carbon atom may be combined to form—(CH₂)_(v)— wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected from C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:

[0127] a) C₁₋₄ alkoxy,

[0128] b) aryl or heterocycle,

[0129] c) halogen,

[0130] d) HO,

[0131] e)

[0132] f) —SO₂R¹¹ or

[0133] g) N(R¹⁰)₂;

[0134] R⁶ and R⁷ are independently selected from H; C₁₋₄ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,heteroarylsulfonyl, unsubstituted or substituted with:

[0135] a) C₁₋₄ alkoxy,

[0136] b) aryl or heterocycle,

[0137] c) halogen,

[0138] d) HO,

[0139] e)

[0140] f) —SO₂R¹¹, or

[0141] g) N(R¹⁰)₂, or

[0142] R⁶ and R⁷ may be joined in a ring;

[0143] R⁸ is independently selected from:

[0144] a) hydrogen,

[0145] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹²O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0146] c) C₁-C₆ alkyl unsubstituted or substituted by unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br,R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NH—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹⁰OC(O)NH—;

[0147] R⁹ is selected from:

[0148] a) hydrogen,

[0149] b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br,R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN,NO₂, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0150] c) C₁-C₆ alkyl unsubstituted or substituted by C₁-C₆perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—, CN, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂ orR¹¹OC(O)NR¹⁰—;

[0151] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl,unsubstituted or substituted aryl and unsubstituted or substitutedheterocycle;

[0152] R¹¹ is independently selected from C₁-C₆ alkyl unsubstituted orsubstituted aryl and unsubstituted or substituted heterocycle;

[0153] R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₃perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted orsubstituted aryl, unsubstituted or

[0154] substituted heterocycle, and C₁-C₆ alkyl substituted withunsubstituted or substituted aryl or unsubstituted or substitutedheterocycle;

[0155] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0156] A² is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹I)S(O)₂—, —NR¹OC(O)NR¹°-, S(O)_(m) and—C(R^(1c))₂—;

[0157] W is heteroaryl;

[0158] V is selected from:

[0159] a) heteroaryl, and

[0160] b) aryl;

[0161] X is selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)—O—,—O—C(O)NR¹⁰—, —NR OC(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—and S(O)_(m);

[0162] Z¹ is selected from unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0163] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0164] a) C₁₋₄ alkoxy,

[0165] b) NR⁶R⁷,

[0166] c) C₃₋₆ cycloalkyl,

[0167] d) aryl or heterocycle,

[0168] e) HO,

[0169] f) —S(O)_(m)R⁴, or

[0170] g) —C(O)NR⁶R⁷,

[0171] 2) aryl or heterocycle,

[0172] 3) halogen,

[0173] 4) OR⁶,

[0174] 5) NR⁶R⁷,

[0175] 6) CN,

[0176] 7) NO₂,

[0177] 8) CF₃,

[0178] 9) —S(O)_(m)R⁴,

[0179] 10) —C(O)NR⁶R⁷, or

[0180] 11) C₃-C₆ cycloalkyl;

[0181] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0182] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0183] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0184] a) C₁₋₄ alkoxy,

[0185] b) NR⁶R⁷,

[0186] c) C₃₋₆ cycloalkyl,

[0187] d) aryl or heterocycle,

[0188] e) HO,

[0189] f) —S(O)_(m)R⁴, or

[0190] g) —C(O)NR⁶R⁷,

[0191] 2) aryl or heterocycle,

[0192] 3) halogen,

[0193] 4) OR⁶,

[0194] 5) NR⁶R⁷,

[0195] 6) CN,

[0196] 7) NO₂,

[0197] 8) CF₃,

[0198] 9) —S(O)_(m)R⁴,

[0199] 10) —C(O)NR⁶R⁷, or

[0200] 11) C₃-C₆ cycloalkyl;

[0201] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0202] m is 0, 1 or 2;

[0203] n is 0, 1, 2, 3 or 4;

[0204] p is 0, 1, 2, 3 or 4;

[0205] q is 1 or 2;

[0206] r is 0 to 5;

[0207] s is independently 0, 1, 2 or 3; and

[0208] t is 1, 2, 3, 4, 5, 6 or 7;

[0209] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0210] In a third embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula A:

[0211] wherein:

[0212] R^(1a), R^(1b) and R^(1c) are independently selected fromhydrogen and C₁-C₆ alkyl; R^(1d) and R^(1e) are independently selectedfrom:

[0213] a) hydrogen,

[0214] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O- or —N(R¹⁰)₂, and

[0215] c) unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆ alkynyl,wherein the substituent on the substituted C₁-C₆ alkyl, substitutedC₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected from:unsubstituted or substituted aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆alkenyl, R¹⁰O— and —N(R¹⁰)₂;

[0216] or two R^(1e)s, on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—;

[0217] R⁴ is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstitutedor substituted with:

[0218] a) C₁₋₄ alkoxy,

[0219] b) halogen, or

[0220] c) aryl or heterocycle;

[0221] R⁶ and R⁷ are independently selected from H; C₁₄ alkyl, C₃₋₆cycloalkyl, aryl and heterocycle, unsubstituted or substituted with:

[0222] a) C₁₋₄ alkoxy,

[0223] b) halogen, or

[0224] c) aryl or heterocycle;

[0225] R⁸ is independently selected from:

[0226] a) hydrogen,

[0227] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN, NO₂,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0228] c) C₁-C₆ alkyl substituted by: unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0229] R⁹ is selected from:

[0230] a) hydrogen,

[0231] b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl,R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0232] c) C₁-C₆ alkyl unsubstituted or substituted by C₁-C₆perfluoroalkyl, F, Cl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0233] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl,unsubstituted or substituted aryl and unsubstituted or substitutedheterocycle;

[0234] R¹¹ is independently selected from C₁-C₆ alkyl, unsubstituted orsubstituted aryl and unsubstituted or substituted heterocycle;

[0235] R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₃perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, and C₁-C₆alkyl substituted with unsubstituted or substituted aryl orunsubstituted or substituted heterocycle;

[0236] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and 0;

[0237] A² is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—;

[0238] V is selected from:

[0239] a) heterocycle selected from pyridinyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl, and

[0240] b) aryl;

[0241] W is a heterocycle selected from imidazolyl, pyridinyl, andtriazolyl;

[0242] X and Y are independently selected from —C(O)—, —C(O)NR¹⁰—,—NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—,and S(O)_(m);

[0243] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is independently substituted with one or two of:

[0244] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0245] a) C₁₋₄ alkoxy,

[0246] b) NR⁶R⁷,

[0247] c) C₃₋₆ cycloalkyl,

[0248] d) aryl or heterocycle,

[0249] e) HO,

[0250] f) —S(O)_(m)R⁴, or

[0251] g) —C(O)NR⁶R⁷,

[0252] 2) aryl or heterocycle,

[0253] 3) halogen,

[0254] 4) OR⁶,

[0255] 5) NR⁶R⁷,

[0256] 6) CN,

[0257] 7) NO₂,

[0258] 8) CF₃,

[0259] 9) —S(O)_(m)R⁴,

[0260] 10) —C(O)NR⁶R⁷, or

[0261] 11) C₃-C₆ cycloalkyl;

[0262] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0263] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted independently with one or two of:

[0264] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0265] a) C₁₋₄ alkoxy,

[0266] b) NR⁶R⁷,

[0267] c) C₃₋₆ cycloalkyl,

[0268] d) aryl or heterocycle,

[0269] e) HO,

[0270] f) —S(O)_(m)R⁴, or

[0271] g) —C(O)NR⁶R⁷,

[0272] 2) aryl or heterocycle,

[0273] 3) halogen,

[0274] 4) OR⁶,

[0275] 5) NR⁶R⁷,

[0276] 6) CN,

[0277] 7) NO₂,

[0278] 8) CF₃,

[0279] 9) —S(O)_(m)R⁴,

[0280] 10) —C(O)NR⁶R⁷, or

[0281] 11) C₃-C₆ cycloalkyl;

[0282] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0283] m is 0, 1 or 2;

[0284] n is 0, 1, 2, 3 or 4;

[0285] p is 0, 1, 2, 3 or 4;

[0286] q is 1 or 2;

[0287] r is 0 to 5;

[0288] s is independently 0, 1, 2 or 3; and

[0289] t is 1, 2, 3, 4, 5, 6 or 7;

[0290] or a pharmaceutically acceptable salt or stereoisomer thereof

[0291] In a fourth embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula B:

[0292] wherein:

[0293] R^(1a), R^(1b) and R^(1c) are independently selected from:

[0294] a) hydrogen,

[0295] b) aryl, heterocycle, cycloalkyl, R¹⁰O—, —N(R¹⁰)₂ or C₂-C₆alkenyl, and

[0296] c) C₁-C₆ alkyl unsubstituted or substituted by aryl, heterocycle,C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂; R^(1d) and R^(1e)are independently selected from:

[0297] a) hydrogen,

[0298] b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,(R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—,

[0299] c) unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆ alkynyl,wherein the substituent on the substituted C₁-C₆ alkyl, substitutedC₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected from:unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, halogen, R¹⁰O—,R⁴S(O)_(m)—, R⁴S(O)₂NR¹⁰—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, and R¹⁰OC(O)—NR¹⁰—;

[0300] or two R^(1e)s, on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—;

[0301] R⁴ is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstitutedor substituted with:

[0302] a) C₁₋₄ alkoxy,

[0303] b) halogen, or

[0304] c) aryl or heterocycle;

[0305] R⁶ and R⁷ are independently selected from H; C₁₋₆ alkyl, C₃₋₆cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,heteroarylsulfonyl, unsubstituted or substituted with one or two:

[0306] a) C₁₋₄ alkoxy,

[0307] b) aryl or heterocycle,

[0308] c) halogen,

[0309] d) HO,

[0310] e)

[0311] f) —SO₂R¹¹

[0312] g) N(R¹⁰)₂, or

[0313] h) C₃₋₆ cycloalkyl;

[0314] R⁸ is independently selected from:

[0315] a) hydrogen,

[0316] b) unsubstituted or substituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0317] c) C₁-C₆ alkyl substituted by: unsubstituted or substituted aryl,C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0318] R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆perfluoroalkyl,

[0319] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyland unsubstituted or substituted aryl;

[0320] R¹¹ is independently selected from C₁-C₆ alkyl and unsubstitutedor substituted aryl;

[0321] R¹² is independently selected from hydrogen, C₁-C₆ alkyl,unsubstituted or substituted benzyl, unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, and C₁-C₆ alkyl substitutedwith unsubstituted or substituted aryl or unsubstituted or substitutedheterocycle;

[0322] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0323] A² is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—;

[0324] V is selected from:

[0325] a) heterocycle selected from pyridinyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl, and

[0326] b) aryl;

[0327] X is selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);

[0328] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heterocycle, wherein the substituted arylor substituted heterocycle is independently substituted with one or twoof:

[0329] 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0330] a) C₁₋₄ alkoxy,

[0331] b) NR⁶R⁷,

[0332] c) C₃₋₆ cycloalkyl,

[0333] d) aryl or heterocycle,

[0334] e) HO,

[0335] f) —S(O)_(m)R⁴,

[0336] g) —C(O)NR⁶R⁷, or

[0337] h) C₁₋₄ perfluoroalkyl;

[0338] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0339] 3) halogen,

[0340] 4) OR⁶,

[0341] 5) NR⁶R⁷,

[0342] 6) CN,

[0343] 7) NO₂,

[0344] 8) CF₃,

[0345] 9) —S(O)_(m)R⁴,

[0346] 10) —OS(O)₂R⁴,

[0347] 11) —C(O)NR⁶R⁷,

[0348] 12) —C(O)OR⁶, or

[0349] 13) C₃-C₆ cycloalkyl;

[0350] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0351] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0352] 1) C₁-8 alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0353] a) C₁₋₄ alkoxy,

[0354] b) NR⁶R⁷,

[0355] c) C₃₋₆ cycloalkyl,

[0356] d) aryl or heterocycle,

[0357] e) HO,

[0358] f) —S(O)_(m)R⁴,

[0359] g) —C(O)NR⁶R⁷, or

[0360] h) C₁₋₄perfluoroalkyl;

[0361] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0362] 3) halogen,

[0363] 4) OR⁶,

[0364] 5) NR⁶R⁷,

[0365] 6) CN,

[0366] 7) NO₂,

[0367] 8) CF₃,

[0368] 9) —S(O)_(m)R⁴,

[0369] 10) —OS(O)₂R⁴,

[0370] 11) —C(O)NR⁶R⁷,

[0371] 12) —C(O)OR⁶, or

[0372] 13) C₃-C₆ cycloalkyl;

[0373] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0374] m is 0, 1 or 2;

[0375] n is 0, 1, 2, 3 or 4;

[0376] p is 0, 1, 2, 3 or 4;

[0377] r is 0 to 5;

[0378] s is 0, 1, 2 or 3; and

[0379] t is 1, 2, 3, 4, 5, 6 or 7;

[0380] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0381] In a fifth embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula B:

[0382] wherein:

[0383] R^(1a), R^(1b) and R^(1c) are independently selected fromhydrogen or C₁-C₆ alkyl;

[0384] R^(1d) and R^(1e) are independently selected from:

[0385] a) hydrogen,

[0386] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O— or —N(R¹⁰)₂, and

[0387] c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂;

[0388] or two R^(1e)s on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—;

[0389] R⁴ is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstitutedor substituted with:

[0390] a) C₁₋₄ alkoxy,

[0391] b) halogen, or

[0392] c) aryl or heterocycle;

[0393] R⁶ and R⁷ are independently selected from:

[0394] a) hydrogen,

[0395] b) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— orR¹⁰OC(O)— and

[0396] c) C₁-C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—;

[0397] R⁸ is independently selected from:

[0398] a) hydrogen,

[0399] b) unsubstituted or substituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0400] c) C₁-C₆ alkyl substituted by: unsubstituted or substituted aryl,C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰), R¹⁰C(O)—,—N(R¹⁰)₂, or R ¹ OC(O)NR¹⁰—;

[0401] R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆perfluoroalkyl;

[0402] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyland unsubstituted or substituted aryl;

[0403] R¹¹ is independently selected from C₁-C₆ alkyl and unsubstitutedor substituted aryl;

[0404] R¹² is independently selected from hydrogen, C₁-C₆ alkyl,unsubstituted or substituted benzyl, unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, and C₁-C₆ alkyl substitutedwith unsubstituted or substituted aryl or unsubstituted or substitutedheterocycle;

[0405] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0406] A² is selected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—;

[0407] V is selected from:

[0408] a) heteroaryl selected from imidazolyl, pyridinyl, thiazolyl,indolyl, quinolinyl, isoquinolinyl, and thienyl, and

[0409] b) aryl;

[0410] X is selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);

[0411] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is independently substituted with one or two of:

[0412] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0413] a) C₁₋₄ alkoxy,

[0414] b) NR⁶R⁷,

[0415] c) C₃₋₆ cycloalkyl,

[0416] d) aryl or heterocycle,

[0417] e) HO,

[0418] f) —S(O)_(m)R⁴, or

[0419] g) —C(O)NR⁶R⁷,

[0420] 2) aryl or heterocycle,

[0421] 3) halogen,

[0422] 4) OR⁶,

[0423] 5) NR⁶R⁷,

[0424] 6) CN,

[0425] 7) NO₂,

[0426] 8) CF₃,

[0427] 9) —S(O)_(m)R⁴,

[0428] 10) —C(O)NR⁶R⁷, or

[0429] 11) C₃-C₆ cycloalkyl;

[0430] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0431] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0432] 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0433] a) C₁₋₄ alkoxy,

[0434] b) NR⁶R⁷,

[0435] c) C₃₋₆ cycloalkyl,

[0436] d) aryl or heterocycle,

[0437] e) HO,

[0438] f) —S(O)_(m)R⁴,

[0439] g) —C(O)NR⁶R⁷, or

[0440] h) C₁₋₄ perfluoroalkyl;

[0441] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0442] 3) halogen,

[0443] 4) OR⁶,

[0444] 5) NR⁶R⁷,

[0445] 6) CN,

[0446] 7) NO₂,

[0447] 8) CF₃,

[0448] 9) —S(O)_(m)R⁴,

[0449] 10) —OS(O)₂R⁴,

[0450] 11) —C(O)NR⁶R⁷,

[0451] 12) —C(O)OR⁶, or

[0452] 13) C₃-C₆ cycloalkyl;

[0453] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0454] m is 0, 1 or 2;

[0455] n is 0, 1, 2, 3 or 4;

[0456] p is 0, 1, 2, 3 or 4;

[0457] r is 0 to 5;

[0458] s is independently 0, 1, 2 or 3; and

[0459] t is 1, 2, 3, 4, 5, 6 or 7;

[0460] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0461] Another embodiment of the compounds of this invention isillustrated by the formula C:

[0462] wherein:

[0463] g is CH or N;

[0464] R^(1a), R^(1b) and R^(1c) are independently selected fromhydrogen or C₁-C₆ alkyl;

[0465] R^(1d) and R^(1e) are independently selected from:

[0466] a) hydrogen,

[0467] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O— or —N(R¹⁰)₂, and

[0468] c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂;

[0469] or two R^(1e)s on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—;

[0470] R⁴ is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstitutedor substituted with:

[0471] a) C₁₋₄ alkoxy,

[0472] b) halogen, or

[0473] c) aryl or heterocycle;

[0474] R⁶ and R⁷ are independently selected from:

[0475] a) hydrogen,

[0476] b) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— orR¹⁰OC(O)— and

[0477] c) C₁-C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰C(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—;

[0478] R⁸ is independently selected from:

[0479] a) hydrogen,

[0480] b) unsubstituted or substituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0481] c) C₁-C₆ alkyl substituted by unsubstituted or substituted aryl,C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0482] R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆perfluoroalkyl;

[0483] R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyland unsubstituted or substituted aryl;

[0484] R¹¹ is independently selected from C₁-C₆ alkyl and unsubstitutedor substituted aryl;

[0485] R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₃perfluoroalkyl, unsubstituted or substituted benzyl, unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, and C₁-C₆alkyl substituted with unsubstituted or substituted aryl orunsubstituted or substituted heterocycle;

[0486] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0487] A² is selected from a bond, —C(O)—, —C(O)NR¹ ¹⁰—, —NR¹⁰C(O)—, O,—N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—;

[0488] X is selected from: —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—, and S(O)_(m);

[0489] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or two of:

[0490] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0491] a) C₁₋₄ alkoxy,

[0492] b) NR⁶R⁷,

[0493] c) C₃₋₆ cycloalkyl,

[0494] d) aryl or heterocycle,

[0495] e) HO,

[0496] f) —S(O)_(m)R⁴, or

[0497] g) —C(O)NR⁶R⁷,

[0498] 2) aryl or heterocycle,

[0499] 3) halogen,

[0500] 4) OR⁶,

[0501] 5) NR⁶R⁷,

[0502] 6) CN,

[0503] 7) NO₂,

[0504] 8) CF₃,

[0505] 9) —S(O)_(m)R⁴,

[0506] 10) —C(O)NR⁶R⁷, or

[0507] 11) C₃-C₆ cycloalkyl;

[0508] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0509] Z² is selected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of:

[0510] 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted orsubstituted with:

[0511] a) C₁₋₄ alkoxy,

[0512] b) NR⁶R⁷,

[0513] c) C₃₋₆ cycloalkyl,

[0514] d) aryl or heterocycle,

[0515] e) HO,

[0516] f) —S(O)_(m)R⁴,

[0517] g) —C(O)NR⁶R⁷, or

[0518] h) C₁₋₄perfluoroalkyl;

[0519] 2) substituted or unsubstituted aryl or substituted orunsubstituted heterocycle,

[0520] 3) halogen,

[0521] 4) OR⁶,

[0522] 5) NR⁶R⁷,

[0523] 6) CN,

[0524] 7) NO₂,

[0525] 8) CF₃,

[0526] 9) —S(O)_(m)R⁴,

[0527] 10) —OS(O)₂R⁴,

[0528] 11) —C(O)NR⁶R⁷,

[0529] 12) —C(O)OR⁶, or

[0530] 13) C₃-C₆ cycloalkyl;

[0531] provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0532] m is 0, 1 or 2;

[0533] n is 0, 1, 2, 3 or 4;

[0534] p is 0, 1, 2, 3 or 4;

[0535] r is 0 to 5;

[0536] s is independently 0, 1, 2 or 3; and

[0537] t is 1, 2, 3, 4, 5, 6 or 7;

[0538] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0539] In another embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula D:

[0540] wherein:

[0541] R^(1b) and R¹c are independently selected from hydrogen or C₁-C₆alkyl;

[0542] R^(1d) and R¹e are independently selected from:

[0543] a) hydrogen,

[0544] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O— or —N(R¹⁰), and

[0545] c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂;

[0546] or two R^(1e)s on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected from C₁₋₄ alkyl and C₃₋₆cycloalkyl, unsubstituted or substituted with:

[0547] a) C₁₋₄ alkoxy,

[0548] b) halogen, or

[0549] c) aryl or heterocycle;

[0550] R⁶ and R⁷ are independently selected from:

[0551] a) hydrogen,

[0552] b) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— orR¹⁰OC(O)— and

[0553] c) C₁-C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—;

[0554] R⁸ is independently selected from:

[0555] a) hydrogen,

[0556] b) unsubstituted or substituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0557] c) C₁-C₆ alkyl substituted by unsubstituted or substituted aryl,C₁-C₆ perfluoroalkyl, R¹⁰O, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0558] R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆perfluoroalkyl;

[0559] R¹⁰ and R¹² are independently selected from hydrogen, C₁-C₆alkyl, benzyl and unsubstituted or substituted aryl;

[0560] R¹¹ is independently selected from C₁-C₆ alkyl and unsubstitutedor substituted aryl;

[0561] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0562] X is selected from: —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);

[0563] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or two of:

[0564] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0565] a) C₁₋₄ alkoxy,

[0566] b) NR⁶R⁷,

[0567] c) C₃₋₆ cycloalkyl,

[0568] d) aryl or heterocycle,

[0569] e) HO,

[0570] f) —S(O)_(m)R⁴, or

[0571] g) —C(O)NR⁶R⁷,

[0572] 2) aryl or heterocycle,

[0573] 3) halogen,

[0574] 4) OR⁶,

[0575] 5) NR⁶R⁷,

[0576] 6) CN,

[0577] 7) NO₂,

[0578] 8) CF₃,

[0579] 9) —S(O)_(m)R⁴,

[0580] 10) —C(O)NR⁶R⁷, or

[0581] 11) C₃-C₆ cycloalkyl;

[0582] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0583] m is 0, 1 or 2;

[0584] n is 0, 1, 2, 3 or 4;

[0585] p is 0, 1, 2, 3 or 4;

[0586] r is 0 to 5;

[0587] s is independently 0, 1, 2 or 3; and

[0588] t is 1, 2, 3, 4, 5, 6 or 7;

[0589] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0590] In another embodiment of this invention, the inhibitors ofprenyl-protein transferase are illustrated by the formula E:

[0591] wherein:

[0592] R^(1b) and R^(1c) are independently selected from hydrogen orC₁-C₆ alkyl;

[0593] R^(1d) is selected from:

[0594] a) hydrogen,

[0595] b) aryl, heterocycle or C₃-C₁₀ cycloalkyl, and

[0596] c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂;

[0597] R^(1e) is independently selected from:

[0598] a) hydrogen,

[0599] b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O—, —N(R¹⁰)₂ or C₂-C₆alkenyl, and

[0600] c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂;

[0601] or two R^(1e)s on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—;

[0602] R⁴ is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstitutedor substituted with:

[0603] a) C₁₋₄ alkoxy,

[0604] b) halogen, or

[0605] c) aryl or heterocycle;

[0606] R⁶ and R⁷ are independently selected from:

[0607] a) hydrogen,

[0608] b) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— orR¹⁰OC(O)— and

[0609] c) C₁-C₆ alkyl substituted by C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—;

[0610] R⁸ is independently selected from:

[0611] a) hydrogen,

[0612] b) unsubstituted or substituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and

[0613] c) C₁-C₆ alkyl substituted by unsubstituted or substituted aryl,C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;

[0614] R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆perfluoroalkyl;

[0615] R¹⁰ and R¹² are independently selected from hydrogen, C₁-C₆alkyl, benzyl and unsubstituted or substituted aryl;

[0616] R¹¹ is independently selected from C₁-C₆ alkyl and unsubstitutedor substituted aryl;

[0617] A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O;

[0618] X is selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);

[0619] Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or two of:

[0620] 1) C₁₋₄ alkyl, unsubstituted or substituted with:

[0621] a) C₁₋₄ alkoxy,

[0622] b) NR⁶R⁷,

[0623] c) C₃₋₆ cycloalkyl,

[0624] d) aryl or heterocycle,

[0625] e) HO,

[0626] f) —S(O)_(m)R⁴, or

[0627] g) —C(O)NR⁶R⁷,

[0628] 2) aryl or heterocycle,

[0629] 3) halogen,

[0630] 4) OR⁶,

[0631] 5) NR⁶R⁷,

[0632] 6) CN,

[0633] 7) NO₂,

[0634] 8) CF₃,

[0635] 9) —S(O)_(m)R⁴,

[0636] 10) —C(O)NR⁶R⁷, or

[0637] 11) C₃-C₆ cycloalkyl;

[0638] provided that Z¹ is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl;

[0639] m is 0, 1 or 2;

[0640] n is 0, 1, 2, 3 or 4;

[0641] p is 0, 1, 2, 3 or 4; provided p is 1, 2, 3 or 4 when X is—NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)— or N(R¹⁰)S(O)₂—;

[0642] r is 0 to 5;

[0643] s is independently 0, 1, 2 or 3; and

[0644] t is 1, 2, 3, 4, 5, 6 or 7;

[0645] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0646] Examples of the compounds of the invention are:

[0647]5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[11.3.1.1^(3,7)]octadeca-1(16),3(18),4,6,13(17),14-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;

[0648]5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3(20),4,6,15(19),16-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;

[0649] 5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;

[0650]5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-(16-spiro-(2-cyclohexanone)tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;

[0651]14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile;

[0652]15-Amino-15-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[14.3.1.1^(3,7)]heneicosa-1(20),3,5,7(21),16.18-hexaene-19-carbonitrile;

[0653]14-amino-14-(3-methyl-3H-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

[0654] or the free bases, the pharmaceutically acceptable salts orstereoisomers thereof.

[0655] Specific example of the compounds of the instant inventioninclude:

[0656] 14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile;

[0657] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0658] The compounds of the present invention may have asymmetriccenters, chiral axes and chiral planes, and occur as racemates, racemicmixtures, and as individual diastereomers, with all possible isomers,including optical isomers, being included in the present invention. (SeeE. L. Eliel and S. H. Wilen Stereochemistry of Carbon Compounds (JohnWiley and Sons, New York 1994), in particular pages 1119-1190) When anyvariable (e.g. aryl, heterocycle, R^(1a), R⁶ etc.) occurs more than onetime in any constituent, its definition on each occurrence isindependent at every other occurrence. Also, combinations ofsubstituents/or variables are permissible only if such combinationsresult in stable compounds.

[0659] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms; “alkoxy” represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Halogen” or “halo” as used herein means fluoro, chloro, bromo and iodo.

[0660] Preferably, alkenyl is C₂-C₆ alkenyl.

[0661] Preferably, alkynyl is C₂-C₆ alkynyl.

[0662] As used herein, “cycloalkyl” is intended to include cyclicsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms. Preferably, cycloalkyl is C₃-C₁₀ cycloalkyl. Examples ofsuch cycloalkyl elements include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0663] As used herein, “aryl” is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic. Examples of such aryl elements includephenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl,anthryl or acenaphthyl.

[0664] The term heterocycle or heterocyclic, as used herein, representsa stable 5- to 7-membered monocyclic or stable 8- to 11-memberedbicyclic heterocyclic ring which is either saturated or unsaturated, andwhich consists of carbon atoms and from one to four heteroatoms selectedfrom the group consisting of N, O, and S, and including any bicyclicgroup in which any of the above-defined heterocyclic rings is fused to abenzene ring. The heterocyclic ring may be attached at any heteroatom orcarbon atom which results in the creation of a stable structure. Theterm heterocycle or heterocyclic, as used herein, includes heteroarylmoieties. Examples of such heterocyclic elements include, but are notlimited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, 2-pyridinonyl, pyrazinyl, pyrazolidinyl,pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl and triazolyl.

[0665] As used herein, “heteroaryl” is intended to mean any stablemonocyclic or bicyclic carbon ring of up to 7 members in each ring,wherein at least one ring is aromatic and wherein from one to fourcarbon atoms are replaced by heteroatoms selected from the groupconsisting of N, O, and S. Examples of such heterocyclic elementsinclude, but are not limited to, benzimidazolyl, benzisoxazolyl,benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl,oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl,thienothienyl, thienyl and triazolyl.

[0666] As used herein, unless otherwise specifically defined,substituted alkyl, substituted cycloalkyl, substituted aroyl,substituted aryl, substituted heteroaroyl, substituted heteroaryl,substituted arylsulfonyl, substituted heteroarylsulfonyl and substitutedheterocycle include moieties containing from 1 to 3 substituents inaddition to the point of attachment to the rest of the compound.Preferably, such substituents are selected from the group which includesbut is not limited to F, Cl, Br, CF₃, NH2, N(C₁-C₆ alkyl)₂, NO2, CN,(C₁-C₆ alkyl)O—, (aryl)O—, —OH, (C₁-C₆ alkyl)S(O)_(m)—, (C₁-C₆alkyl)C(O)NH—, H2N—C(NH)—, (C₁-C₆ alkyl)C(O)—, (C₁-C₆ alkyl)OC(O)—,N3,(C₁-C₆ alkyl)OC(O)NH—, phenyl, pyridyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C1-C20 alkyl.

[0667] Preferably, as used herein in the definition of R⁶ and R⁷, thesubstituted C₁₋₆ alkyl, substituted C₂₋₆ alkenyl, substituted C₂₋₆alkynyl, substituted C₃₋₆ cycloalkyl, substituted aroyl, substitutedaryl, substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroarylsulfonyl, substituted heterocycle and substituted C₆₋₁₀multicyclic alkyl ring, include moieties containing from 1 to 3substituents in addition to the point of attachment to the rest of thecompound.

[0668] The moiety formed when, in the definition of R^(1a), R^(1b),R^(1c), R^(1d) and R^(1e), two R^(1a)s, two R^(1b)s, two R^(1c)s, twoR^(1d)s or two R^(1e)s, on the same carbon atom are combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—, is illustrated by, but not limited to, thefollowing:

[0669] The moiety formed when, in the definition of R⁶ and R⁷, R⁶ and R⁷are joined to form a ring, is illustrated by, but not limited to, thefollowing:

[0670] Lines drawn into the ring systems from substituents (such as fromR⁸, R⁹ etc.) indicate that the indicated bond may be attached to any ofthe substitutable ring carbon and nitrogen atoms.

[0671] Preferably, R^(1a) and R^(1b) are independently selected from:hydrogen, —N(R¹⁰)₂, R¹⁰C(O)NR¹⁰— or unsubstituted or substituted C₁-C₆alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selectedfrom unsubstituted or substituted phenyl, —N(R¹⁰)₂, R¹⁰O— andR¹⁰C(O)NR¹⁰—. More preferably, R^(1a) and R^(1b) are hydrogen.

[0672] Preferably, R^(1c) is independently selected from: hydrogen, orunsubstituted or substituted C₁-C₆ alkyl wherein the substituent on thesubstituted C₁-C₆ alkyl is selected from unsubstituted or substitutedphenyl, —N(R¹⁰)₂, R¹⁰O— and R¹⁰C(O)NR¹⁰—.

[0673] Preferably, R^(1e) is selected from:

[0674] a) hydrogen,

[0675] b) substituted or unsubstituted aryl, substituted orunsubstituted heterocycle, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, R¹⁰O—, —N(R¹⁰)₂, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, or R¹⁰OC(O)—, and

[0676] c) unsubstituted or substituted C₁-C₆ alkyl wherein thesubstituent on the substituted C₁-C₆ alkyl is selected from substitutedor unsubstituted aryl, substituted or unsubstituted heterocycle, halo,perfluoroalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—,R⁴S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, (R¹⁰)₂N—C(NR¹⁰)—,R⁴S(O)₂NR¹⁰—, —S(O)₂N(R¹⁰)₂, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, andR¹¹OC(O)—NR¹⁰—;

[0677] or two R^(1e)s on the same carbon atom may be combined to form—(CH₂)_(v)——, wherein one of the CH₂ moieties is optionally replacedwith —C(═O)—, —NH— or —NHC(═O)—.

[0678] Preferably, R^(1d) is selected from:

[0679] a substituted or unsubstituted aryl, substituted or unsubstitutedheterocycle, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—,—N(R¹⁰)₂, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, or R¹⁰OC(O)—, and

[0680] b unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆ alkynyl,wherein the substituent on the substituted C₁-C₆ alkyl, substitutedC₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected from substitutedor unsubstituted aryl, substituted or unsubstituted heterocycle, halo,C₁-C₆ perfluoroalkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,R¹⁰O—, R⁴S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, (R¹⁰)₂N—C(NR¹⁰)—,R⁴S(O)₂NR¹⁰—, —S(O)₂N(R¹⁰)₂, R¹C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, andR¹¹OC(O)—NR¹⁰—.

[0681] Preferably, R⁴ is C₁-C₆ alkyl.

[0682] Preferably, R⁶ and R⁷ is selected from: hydrogen, unsubstitutedor substituted C₁-C₆ alkyl, unsubstituted or substituted aryl andunsubstituted or substituted cycloalkyl.

[0683] Preferably, R⁹ and R^(9a) are hydrogen or methyl.

[0684] Preferably, R¹⁰ is selected from H, C₁-C₆ alkyl and benzyl.

[0685] Preferably, A¹ and A² are independently selected from a bond,—C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —NR1 OC(O)NR¹⁰—, —S(O)₂N(R¹⁰)— and—N(R¹⁰)S(O)₂—. More preferably, A¹ is selected from a bond and O. Morepreferably, A² is a bond.

[0686] Preferably, V is selected from heteroaryl and aryl. Morepreferably, V is phenyl or pyridyl.

[0687] Preferably, X is selected from —NR¹⁰C(O)—, O, —N(R¹⁰)— and—N(R¹⁰)S(O)₂—.

[0688] Preferably, Z¹ is selected from unsubstituted or substituted aryland unsubstituted or substituted heteroaryl. More preferably, Z¹ isselected from unsubstituted or substituted phenyl, unsubstituted orsubstituted naphthyl, unsubstituted or substituted pyridyl,unsubstituted or substituted furanyl and unsubstituted or substitutedthienyl. Still more preferably, Z¹ is selected from unsubstituted orsubstituted phenyl and unsubstituted or substituted naphthyl.

[0689] Preferably, Z² is selected from a bond, unsubstituted orsubstituted aryl and unsubstituted or substituted heteroaryl. Morepreferably, Z² is selected from a bond, unsubstituted or substitutedphenyl, unsubstituted or substituted naphthyl, unsubstituted orsubstituted pyridyl, unsubstituted or substituted furanyl andunsubstituted or substituted thienyl. Still more preferably, Z² isselected from a bond and unsubstituted or substituted phenyl.

[0690] Preferably, W is selected from imidazolyl, pyridinyl andtriazolyl. More preferably, W is selected from imidazolyl and pyridyl.

[0691] Preferably, n is 0, 1,or 2.

[0692] Preferably, r is 1 or 2.

[0693] Preferably p is 0, 1 or 2.

[0694] Preferably s is 0 or 1.

[0695] Preferably, the moiety

[0696] is selected from:

[0697] wherein R^(9a) is selected from hydrogen and methyl.

[0698] It is intended that the definition of any substituent or variable(e.g., R^(1a), R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,—N(R¹⁰)₂ represents —NHH, —NHCH₃, —NHC₂H₅, etc. It is understood thatsubstituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art, as well as those methods set forthbelow, from readily available starting materials.

[0699] The pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed, e.g., from non-toxic inorganic or organicacids. For example, such conventional non-toxic salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like: and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

[0700] The pharmaceutically acceptable salts of the compounds of thisinvention can be synthesized from the compounds of this invention whichcontain a basic moiety by conventional chemical methods. Generally, thesalts are prepared either by ion exchange chromatography or by reactingthe free base with stoichiometric amounts or with an excess of thedesired salt-forming inorganic or organic acid in a suitable solvent orvarious combinations of solvents.

[0701] Reactions used to generate the compounds of this invention areprepared by employing reactions as shown in the Schemes 1-13, inaddition to other standard manipulations such as ester hydrolysis,cleavage of protecting groups, etc., as may be known in the literatureor exemplified in the experimental procedures. Substituents R^(sub) andR^(sub′), as shown in the Schemes, represent the substituents on Z¹ andZ² and other moieties of the instant compounds; however their point ofattachment to the ring is illustrative only and is not meant to belimiting. It is understood that one of ordinary skill in the art wouldbe readily able to substitute commercially available or readily preparedsuitably substituted aromatic moieties for those unsubstituted moietiesillustrated in the schemes.

[0702] These reactions may be employed in a linear sequence to providethe compounds of the invention or they may be used to synthesizefragments which are subsequently joined by the alkylation reactionsdescribed in the Schemes.

[0703] Synopsis of Schemes 1-13:

[0704] The requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures. InScheme 1, for example, the synthesis of a key intermediate in thepreparation of macrocyclic compounds of the instant invention and itsincorporation into the macrocycle is generally outlined. A suitablysubstituted halohydroxytoluene I is oxidized and reacted with a suitablysubstituted nucleophilic heteroaryl moiety to form the intermediate III.Intermediate III is oxidized to key intermediate IV, which may bealkylated to key hydroxy intermediate V. Intermediate V may be utilizedin the synthesis of the macrocyclic compound or the hydroxyl may befurther elaborated to the corresponding amine VI as shown. The Schemeillustrates the formation of a macrocyclic compound wherein “X” is anamide moiety. Coupling of amine VI to a phenolic alkanoic acid, followedby deprotection of the phenol and cesium carbonate mediated couplingprovides the instant compound VII. This last cyclization reactiondepends on the presence of an electron withdrawing moiety (such asnitro, cyano, and the like) either ortho or para to the halogen atom.

[0705] Scheme 2 illustrates the synthesis of a compound of the instantinvention wherein W is the preferred imidazolyl moiety. Thus, the tritylprotected halo imidazolyl is reacted with the aldehyde II to provide thealcohol VIII. The imidazolyl may be alkylated on the nitrogen, in aseries of steps, and then the hydroxy moiety is oxidized to the ketoneIX. The ketone IX may be further functionalized to intermediates X andXI, as illustrated in Scheme I and elaborated to the instant compoundXII.

[0706] Scheme 3 illustrated the preparation of the instant compoundwherein “X” is an ester moiety as in compound XIII.

[0707] The alkanoic acid utilized in Scheme 1 may be converted to thealdehyde XIV, as shown in Scheme 4, which may then be utilized toreductively alkylate key intermediate XI. The resulting amine may bealkylated as shown, then may undergo the previously described steps toprovide the instant compound XV.

[0708] If allyl Grignard is reacted with intermediate IX, the resultingallyl compound may be oxidized to provide the key intermediate aldehydeXVI, as shown in Scheme 5. Protection of the hydroxyl moiety providesintermediate XVII, which may then be used to reductively alkylate avariety of suitably substituted amines, such as the commerciallyavailable aminobenzylthiophenol shown. The previously illustrated stepsthen lead to the instant compound XVIII.

[0709] As shown in Scheme 6, intermediate IX may alternatively beconverted to the protected imine XIX, which may also react with allylGrignard to provide, after oxidation intermediate XX. Intermediate XXmay then be reacted with an amine to eventually provide the instantcompound XXI.

[0710] The benzyl protected intermediate XVIIa may be alternativelyoxidized to the carboxylic acid XXII, which may be converted to the acidchloride XXIII, as illustrated in Scheme 7. This acid chloride may bereacted with a suitably substituted aminomethylphenol, such as the mesylprotected compound XXIV, to provide intermediate XXV. The previouslyillustrated cyclization conditions deprotect the phenol moiety andcyclize to provide, after further oxygen deprotection instant compoundXXVI, which may be reduced to provide instant compound XXVII.

[0711] Incorporation of a sulfur containing moiety for A¹ in the instantcompounds is illustrated in Scheme 8. Thus the acid chloride XXIII isreacted with the disulfide protected aniline XXVIII to provide theintermediate XXIX. The sulfide moiety is liberated with dithiothrietolto provide the mercaptan, which undergoes cyclization under cesiumcarbonate conditions to provide the instant compound XXX. The sulfur maybe oxidized to either the sulfone or sulfoxide XXXI.

[0712] Scheme 9 illustrates incorporation of a naphthyl moiety for “Z¹”.

[0713] Incorporation of a nitrogen-containing moiety for “A¹” isillustrated in Scheme 10. Thus, the aldehyde of intermediate XVII may beconverted to the homologous amine in intermediate XXXII. IntermediateXXXII may be reacted with a suitably substituted acid chloride XXXIII toprovide compound XXXIV, which can be deprotected and cyclized in thepresence of potassium t-butoxide to provide the instant compound XXXV.

[0714] Scheme 11 illustrates the synthesis of the instant compound XXXVIwherein “X” is a sulfonamide moiety.

[0715] Scheme 12 illustrates the synthetic strategy that is employedwhen the R⁸ substituent is not an electronic withdrawing moiety eitherortho or para to the fluorine atom. In the absence of the electronwithdrawing moiety, the intramolecular cyclization can be accomplishedvia an Ullmann reaction. Thus, a suitably substituted iodo benzaldehydeXXXVII may be employed in place of intermediate II. Incorporation of a“W” moiety, in this instance a pyridyl group, followed by the previouslydescribed elaboration provides the intermediate XXXVIII. Intramolecularcyclization may then be affected under Ullmann conditions to provide theinstant compound IXL.

[0716] Use of intermediate XI to provide an instant compound having asulfonamide moiety for “X” is illustrated in Scheme 13.

[0717] In a preferred embodiment of the instant invention the compoundsof the invention are selective inhibitors of farnesyl-proteintransferase. A compound is considered a selective inhibitor offarnesyl-protein transferase, for example, when its in vitrofarnesyl-protein transferase inhibitory activity, as assessed by theassay described in Example 8, is at least 100 times greater than the invitro activity of the same compound against geranylgeranyl-proteintransferase-type I in the assay described in Example 9. Preferably, aselective compound exhibits at least 1000 times greater activity againstone of the enzymatic activities when comparing geranylgeranyl-proteintransferase-type I inhibition and farnesyl-protein transferaseinhibition.

[0718] It is also preferred that the selective inhibitor offarnesyl-protein transferase is further characterized by:

[0719] a) an IC₅₀ (a measure of in vitro inhibitory activity) forinhibition of the prenylation of newly synthesized K-Ras protein morethan about 100-fold higher than the EC₅₀ for the inhibition of thefarnesylation of hDJ protein.

[0720] When measuring such IC₅₀s and EC₅₀s the assays described inExample 13 may be utilized.

[0721] It is also preferred that the selective inhibitor offarnesyl-protein transferase is further characterized by:

[0722] b) an IC₅₀ (a measurement of in vitro inhibitory activity) forinhibition of K4B-Ras dependent activation of MAP kinases in cells atleast 100-fold greater than the IC₅₀ for inhibition of the farnesylationof the protein hDJ in cells.

[0723] It is also preferred that the selective inhibitor offarnesyl-protein transferase is further characterized by:

[0724] c) an IC₅₀ (a measurement of in vitro inhibitory activity)against H-Ras dependent activation of MAP kinases in cells at least 1000fold lower than the inhibitory activity (IC₅₀) against H-ras-CVLL(SEQ.ID.NO.: 1) dependent activation of MAP kinases in cells.

[0725] When measuring Ras dependent activation of MAP kinases in cellsthe assays described in Example 12 may be utilized.

[0726] In another preferred embodiment of the instant invention thecompounds of the invention are dual inhibitors of farnesyl-proteintransferase and geranylgeranyl-protein transferase type I. Such a dualinhibitor may be termed a Class II prenyl-protein transferase inhibitorand will exhibit certain characteristics when assessed in in vitroassays, which are dependent on the type of assay employed.

[0727] In a SEAP assay, such as described in Examples 12, it ispreferred that the dual inhibitor compound has an in vitro inhibitoryactivity (IC₅₀) that is less than about 12 μM against K4B-Ras dependentactivation of MAP kinases in cells.

[0728] The Class II prenyl-protein transferase inhibitor may also becharacterized by:

[0729] a) an IC₅₀ (a measurement of in vitro inhibitory activity) forinhibiting K4B-Ras dependent activation of MAP kinases in cells between0.1 and 100 times the IC₅₀ for inhibiting the farnesylation of theprotein hDJ in cells; and

[0730] b) an IC₅₀ (a measurement of in vitro inhibitory activity) forinhibiting K4B-Ras dependent activation of MAP kinases in cells greaterthan 5-fold lower than the inhibitory activity (IC₅₀) against expressionof the SEAP protein in cells transfected with the pCMV-SEAP plasmid thatconstitutively expresses the SEAP protein.

[0731] The Class II prenyl-protein transferase inhibitor may also becharacterized by:

[0732] a) an IC₅₀ (a measurement of in vitro inhibitory activity)against H-Ras dependent activation of MAP kinases in cells greater than2 fold lower but less than 20,000 fold lower than the inhibitoryactivity (IC₅₀) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activationof MAP kinases in cells; and

[0733] b) an IC₅₀ (a measurement of in vitro inhibitory activity)against H-ras-CVLL dependent activation of MAP kinases in cells greaterthan 5-fold lower than the inhibitory activity (IC₅₀) against expressionof the SEAP protein in cells transfected with the pCMV-SEAP plasmid thatconstitutively expresses the SEAP protein.

[0734] The Class II prenyl-protein transferase inhibitor may also becharacterized by:

[0735] a) an IC₅₀ (a measurement of in vitro inhibitory activity)against H-Ras dependent activation of MAP kinases in cells greater than10-fold lower but less than 2,500 fold lower than the inhibitoryactivity (IC₅₀) against H-ras-CVLL (SEQ.ID.NO.: 1) dependent activationof MAP kinases in cells; and

[0736] b) an IC₅₀ (a measurement of in vitro inhibitory activity)against H-ras-CVLL dependent activation of MAP kinases in cells greaterthan 5 fold lower than the inhibitory activity (IC₅₀) against expressionof the SEAP protein in cells transfected with the pCMV-SEAP plasmid thatconstitutively expresses the SEAP protein.

[0737] A method for measuring the activity of the inhibitors ofprenyl-protein transferase, as well as the instant combinationcompositions, utilized in the instant methods against Ras dependentactivation of MAP kinases in cells is described in Example 12.

[0738] In yet another embodiment, a compound of the instant inventionmay be a more potent inhibitor of geranylgeranyl-proteintransferase-type I than it is an inhibitor of farnesyl-proteintransferase.

[0739] The instant compounds are useful as pharmaceutical agents formammals, especially for humans. These compounds may be administered topatients for use in the treatment of cancer. Examples of the type ofcancer which may be treated with the compounds of this inventioninclude, but are not limited to, colorectal carcinoma, exocrinepancreatic carcinoma, myeloid leukemias and neurological tumors. Suchtumors may arise by mutations in the ras genes themselves, mutations inthe proteins that can regulate Ras activity (i.e., neurofibromin (NF-1),neu, src, abl, Ick, fyn) or by other mechanisms.

[0740] The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of vision deficitrelated to retinal vascularization.

[0741] The compounds of this invention are also useful for inhibitingother proliferative diseases, both benign and malignant, wherein Rasproteins are aberrantly activated as a result of oncogenic mutation inother genes (i.e., the Ras gene itself is not activated by mutation toan oncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, the composition isuseful in the treatment of neurofibromatosis, which is a benignproliferative disorder.

[0742] The instant compounds may also be useful in the treatment ofcertain viral infections, in particular in the treatment of hepatitisdelta and related viruses (J. S. Glenn et al. Science, 256:1331-1333(1992).

[0743] The compounds of the instant invention are also useful in theprevention of restenosis after percutaneous transluminal coronaryangioplasty by inhibiting neointimal formation (C. Indolfi et al. Naturemedicine, 1:541-545(1995).

[0744] The instant compounds may also be useful in the treatment andprevention of polycystic kidney disease (D. L. Schaffner et al. AmericanJournal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).

[0745] The instant compounds may also be useful for the treatment offungal infections.

[0746] The instant compounds may also be useful as inhibitors ofproliferation of vascular smooth muscle cells and therefore useful inthe prevention and therapy of arteriosclerosis and diabetic vascularpathologies.

[0747] The compounds of the instant invention may also be useful in theprevention and treatment of endometriosis, uterine fibroids,dysfunctional uterine bleeding and endometrial hyperplasia.

[0748] In such methods of prevention and treatment as described herein,the prenyl-protein transferase inhibitors of the instant invention mayalso be co-administered with other well known therapeutic agents thatare selected for their particular usefulness against the condition thatis being treated. For example, the prenyl-protein transferase inhibitormay be useful in farther combination with drugs known to supress theactivity of the ovaries and slow the growth of the endometrial tissue.Such drugs include but are not limited to oral contraceptives,progestins, danazol and GnRH (gonadotropin-releasing hormone) agonists.

[0749] Administration of the prenyl-protein transferase inhibitor mayalso be combined with surgical treatment of endometriosis (such assurgical removal of misplaced endometrial tissue) where appropriate.

[0750] The instant compounds may also be useful as inhibitors of cornealinflammation. These compounds may improve the treatment of cornealopacity which results from cauterization-induced corneal inflammation.The instant compounds may also be useful in reducing corneal edema andneovascularization. (K. Sonoda et al., Invest. Ophthalmol. Vis. Sci.,1998, vol. 39, p 2245-2251).

[0751] The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition, according to standard pharmaceuticalpractice. The compounds can be administered orally or parenterally,including the intravenous, intramuscular, intraperitoneal, subcutaneous,rectal and topical routes of administration.

[0752] Additionally, the compounds of the instant invention may beadministered to a mammal in need thereof using a gel extrusion mechanism(GEM) device, such as that described in U.S. Ser. No. 60/144,643, filedon Jul. 20, 1999, which is hereby incorporated by reference.

[0753] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

[0754] The pharmaceutical compositions containing the active ingredientmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example,microcrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the unpleasant taste ofthe drug or delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a water soluble taste masking material such ashydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delaymaterial such as ethyl cellulose, cellulose acetate buryrate may beemployed.

[0755] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater soluble carrier such as polyethyleneglycol or an oil medium, forexample peanut oil, liquid paraffin, or olive oil.

[0756] Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

[0757] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as butylated hydroxyanisol oralpha-tocopherol.

[0758] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

[0759] The pharmaceutical compositions of the invention may also be inthe form of an oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

[0760] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoring andcoloring agents and antioxidant.

[0761] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

[0762] The sterile injectable preparation may also be a sterileinjectable oil-in-water microemulsion where the active ingredient isdissolved in the oily phase. For example, the active ingredient may befirst dissolved in a mixture of soybean oil and lecithin. The oilsolution then introduced into a water and glycerol mixture and processedto form a microemulation.

[0763] The injectable solutions or microemulsions may be introduced intoa patient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.

[0764] The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

[0765] Compounds of Formula A may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

[0766] For topical use, creams, ointments, jellies, solutions orsuspensions, etc., containing the compound of Formula A are employed.(For purposes of this application, topical application shall includemouth washes and gargles.) The compounds for the present invention canbe administered in intranasal form via topical use of suitableintranasal vehicles and delivery devices, or via transdermal routes,using those forms of transdermal skin patches well known to those ofordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

[0767] When a compound according to this invention is administered intoa human subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, sex and response of the individual patient, as well as theseverity of the patient's symptoms.

[0768] In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

[0769] The compounds of the instant invention may also beco-administered with other well known therapeutic agents that areselected for their particular usefulness against the condition that isbeing treated. For example, the compounds of the instant invention mayalso be co-administered with other well known cancer therapeutic agentsthat are selected for their particular usefulness against the conditionthat is being treated. Included in such combinations of therapeuticagents are combinations of the instant prenyl-protein transferaseinhibitors and an antineoplastic agent. It is also understood that sucha combination of antineoplastic agent and inhibitor of prenyl-proteintransferase may be used in conjunction with other methods of treatingcancer and/or tumors, including radiation therapy and surgery. It isfurther understood that any of the therapeutic agents described hereinmay also be used in combination with a compound of the instant inventionand an antineoplastic agent.

[0770] Examples of an antineoplastic agent include, in general,microtubule-stabilizing agents such as paclitaxel (also known asTaxol®), docetaxel (also known as Taxotere®), epothilone A, epothiloneB, desoxyepothilone A, desoxyepothilone B or their derivatives);microtubule-disruptor agents; alkylating agents, for example, nitrogenmustards, ethyleneimine compounds, alkyl sulfonates and other compoundswith an alkylating action such as nitrosoureas, cisplatin, anddacarbazine; anti-metabolites, for example, folic acid, purine orpyrimidine antagonists; epidophyllotoxin; an antineoplastic enzyme; atopoisomerase inhibitor; procarbazine; mitoxantrone; platinumcoordination complexes; biological response modifiers and growthinhibitors; mitotic inhibitors, for example, vinca alkaloids andderivatives of podophyllotoxin; cytotoxic antibiotics;hormonal/anti-hormonal therapeutic agents, haematopoietic growth factorsand antibodies (such as trastuzumab, also known as Herceptin™).

[0771] Example classes of antineoplastic agents include, for example,the anthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, the taxanes, the epothilones,discodermolide, the pteridine family of drugs, diynenes and thepodophyllotoxins. Particularly useful members of those classes include,for example, doxorubicin, carminomycin, daunorubicin, aminopterin,methotrexate, methopterin, dichloro-methotrexate, mitomycin C,porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosinearabinoside, podophyllotoxin or podo-phyllotoxin derivatives such asetoposide, etoposide phosphate or teniposide, melphalan, vinblastine,vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.Other useful antineoplastic agents include estramustine, cisplatin,carboplatin, cyclophosphamide, bleomycin, tamoxifen, ifosamide,melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate,trimetrexate, dacarbazine, L-asparaginase, dactinomycin, mechlorethamine(nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU),lomustine (CCNU), procarbazine, mitomycin, cytarabine, etoposide,methotrexate, bleomycin, chlorambucil, camptothecin, CPT-11, topotecan,ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindolederivatives, interferons and interleukins. Particular examples ofantineoplastic, or chemotherapeutic, agents are described, for example,by D. J. Stewart in “Nausea and Vomiting: Recent Research and ClinicalAdvances”, Eds. J. Kucharczyk, et al., CRC Press Inc., Boca Raton, Fla.,USA (1991), pages 177-203, especially page 188. See also, R. J. Gralla,et al., Cancer Treatment Reports, 68(1), 163-172 (1984).

[0772] The preferred class of antineoplastic agents is the taxanes andthe preferred antineoplastic agent is paclitaxel.

[0773] The compounds of the instant invention may also beco-administered with antisense oligonucleotides which are specificallyhybridizable with RNA or DNA deriving from human ras gene. Suchantisense oligonucleotides are described in U.S. Pat. No. 5,576,208 andPCT Publ. No. WO 99/22772. The instant compounds are particularly usefulwhen co-administered with the antisense oligonucleotide comprising theamino acid sequence of SEQ.ID.NO: 2 of U.S. Pat. No. 5,576,208.

[0774] Certain compounds of the instant invention may exhibit very lowplasma concentrations and significant inter-individual variation in theplasma levels of the compound. It is believed that very low plasmaconcentrations and high intersubject variability achieved followingadministration of certain prenyl-protein transferase inhibitors tomammals may be due to extensive metabolism by cytochrome P450 enzymesprior to entry of drug into the systemic circulation. Prenyl-proteintransferase inhibitors may be metabolized by cytochrome P450 enzymesystems, such as CYP3A4, CYP2D6, CYP2C9, CYP2C19 or other cytochromeP450 isoform. If a compound of the instant invention demonstrates anaffinity for one or more of the cytochrome P450 enzyme systems, anothercompound with a higher affinity for the P450 enzyme(s) involved inmetabolism should be administered concomitantly. Examples of compoundsthat have a comparatively very high affinity for CYP3A4, CYP2D6, CYP2C9,CYP2C19 or other P450 isoform include, but are not limited to, piperonylbutoxide, troleandomycin, erythromycin, proadifen, isoniazid,allylisopropylacetamide, ethinylestradiol, chloramphenicol,2-ethynylnaphthalene and the like. Such a high affinity compound, whenemployed in combination with a compound of formula A, may reduce theinter-individual variation and increase the plasma concentration of acompound of formula A to a level having substantial therapeutic activityby inhibiting the metabolism of the compound of formula A. Additionally,inhibiting the metabolism of a compound of the instant inventionprolongs the pharmacokinetic half-life, and thus the pharmacodynamiceffect, of the compound.

[0775] A compound of the present invention may be employed inconjunction with antiemetic agents to treat nausea or emesis, includingacute, delayed, late-phase, and anticipatory emesis, which may resultfrom the use of a compound of the present invention, alone or withradiation therapy. For the prevention or treatment of emesis a compoundof the present invention may be used in conjunction with otheranti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3receptor antagonists, such as ondansetron, granisetron, tropisetron, andzatisetron, GABAB receptor agonists, such as baclofen, or acorticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort,Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat.Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,3,928,326 and 3,749,712. For the treatment or prevention of emesis,conjunctive therapy with a neurokinin-l receptor antagonist, a 5HT3receptor antagonist and a corticosteroid is preferred.

[0776] Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications.

[0777] A particularly preferred neurokinin-1 receptor antagonist for usein conjunction with the compounds of the present invention is2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, whichis described in U.S. Pat. No. 5,719,147.

[0778] For the treatment of cancer, it may be desirable to employ acompound of the present invention in conjunction with anotherpharmacologically active agent(s). A compound of the present inventionand the other pharmacologically active agent(s) may be administered to apatient simultaneously, sequentially or in combination. For example, thepresent compound may employed directly in combination with the otheractive agent(s), or it may be administered prior, concurrent orsubsequent to the administration of the other active agent(s). higeneral, the currently available dosage forms of the known therapeuticagents for use in such combinations will be suitable.

[0779] For example, a compound of the present invention may be presentedtogether with another therapeutic agent in a combined preparation, suchas with an antiemetic agent for simultaneous, separate, or sequentialuse in the relief of emesis associated with employing a compound of thepresent invention and radiation therapy. Such combined preparations maybe, for example, in the form of a twin pack. A preferred combinationcomprises a compound of the present invention with antiemetic agents, asdescribed above.

[0780] Radiation therapy, including x-rays or gamma rays which aredelivered from either an externally applied beam or by implantation oftiny radioactive sources, may also be used in combination with theinstant inhibitor of prenyl-protein transferase alone to treat cancer.

[0781] Additionally, compounds of the instant invention may also beuseful as radiation sensitizers, as described in WO 97/38697, publishedon Oct. 23, 1997, and herein incorporated by reference.

[0782] The instant compounds may also be useful in combination withother inhibitors of parts of the signaling pathway that links cellsurface growth factor receptors to nuclear signals initiating cellularproliferation. Thus, the instant compounds may be utilized incombination with farnesyl pyrophosphate competitive inhibitors of theactivity of farnesyl-protein transferase or in combination with acompound which has Raf antagonist activity. The instant compounds mayalso be co-administered with compounds that are selective inhibitors ofgeranylgeranyl protein transferase.

[0783] In particular, if the compound of the instant invention is aselective inhibitor of farnesyl-protein transferase, co-administrationwith a compound(s) that is a selective inhibitor of geranylgeranylprotein transferase may provide an improved therapeutic effect.

[0784] In particular, the compounds disclosed in the following patentsand publications may be useful as farnesyl pyrophosphate-competitiveinhibitor component of the instant composition: U.S. Ser. Nos.08/254,228 and 08/435,047. Those patents and publications areincorporated herein by reference.

[0785] In practicing methods of this invention, which compriseadministering, simultaneously or sequentially or in any order, two ormore of a protein substrate-competitive inhibitor and a farnesylpyrophosphate-competitive inhibitor, such administration can be orallyor parenterally, including intravenous, intramuscular, intraperitoneal,subcutaneous, rectal and topical routes of administration. It ispreferred that such administration be orally. It is more preferred thatsuch administration be orally and simultaneously. When the proteinsubstrate-competitive inhibitor and farnesyl pyrophosphate-competitiveinhibitor are administered sequentially, the administration of each canbe by the same method or by different methods.

[0786] The instant compounds may also be useful in combination with anintegrin antagonist for the treatment of cancer, as described in U.S.Ser. No. 09/055,487, filed Apr. 6, 1998, and WO 98/44797, published onOct. 15, 1998, which are incorporated herein by reference.

[0787] As used herein the term an integrin antagonist refers tocompounds which selectively antagonize, inhibit or counteract binding ofa physiological ligand to an integrin(s) that is involved in theregulation of angiogenisis, or in the growth and invasiveness of tumorcells. In particular, the term refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe αvβ3 integrin, which selectively antagonize, inhibit or counteractbinding of a physiological ligand to the αvβ5 integrin, whichantagonize, inhibit or counteract binding of a physiological ligand toboth the αvβ3 integrin and the αvβ5 integrin, or which antagonize,inhibit or counteract the activity of the particular integrin(s)expressed on capillary endothelial cells. The term also refers toantagonists of the α1β1, α2β1, α5β1, α6β1 and α6β4 integrins. The termalso refers to antagonists of any combination of αvβ3 integrin, αvβ5integrin, α1β1, α2β1, α5β1, α6β1 and α6β4 integrins. The instantcompounds may also be useful with other agents that inhibit angiogenisisand thereby inhibit the growth and invasiveness of tumor cells,including, but not limited to angiostatin and endostatin.

[0788] The instant compounds may also be useful in combination with aninhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-COAreductase) for the treatment of cancer. Compounds which have inhibitoryactivity for HMG-CoA reductase can be readily identified by using assayswell-known in the art. For example, see the assays described or cited inU.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. Theterms “HMG-CoA reductase inhibitor” and “inhibitor of HMG-CoA reductase”have the same meaning when used herein.

[0789] Examples of HMG-CoA reductase inhibitors that may be used includebut are not limited to lovastatin (MEVACOR®; see U.S. Pat. No.4,231,938; 4,294,926; 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. No.4,444,784; 4,820,850; 4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat.Nos. 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772; 4,911,165;4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin(LIPITOR®; see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691;5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (Feb. 5, 1996) and U.S. Pat.Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor asused herein includes all pharmaceutically acceptable lactone andopen-acid forms (i.e., where the lactone ring is opened to form the freeacid) as well as salt and ester forms of compounds which have HMG-CoAreductase inhibitory activity, and therefor the use of such salts,esters, open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

[0790] In HMG-CoA reductase inhibitors where an open-acid form canexist, salt and ester forms may preferably be formed from the open-acid,and all such forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine, omithine,choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenzimidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

[0791] Ester derivatives of the described HMG-CoA reductase inhibitorcompounds may act as prodrugs which, when absorbed into the bloodstreamof a warm-blooded animal, may cleave in such a manner as to release thedrug form and permit the drug to afford improved therapeutic efficacy.

[0792] Similarly, the instant compounds may be useful in combinationwith agents that are effective in the treatment and prevention of NF-1,restenosis, polycystic kidney disease, infections of hepatitis delta andrelated viruses and fungal infections.

[0793] If formulated as a fixed dose, such combination products employthe combinations of this invention within the dosage range describedabove and the other pharmaceutically active agent(s) within its approveddosage range. Combinations of the instant invention may alternatively beused sequentially with known pharmaceutically acceptable agent(s) when amultiple combination formulation is inappropriate.

[0794] The instant compounds may also be useful in combination withprodrugs of antineoplastic agents. In particular, the instant compoundsmay be co-administered either concurrently or sequentially with aconjugate (termed a “PSA conjugate”) which comprises an oligopeptide,that is selectively cleaved by enzymatically active prostate specificantigen (PSA), and an antineoplastic agent. Such co-administration willbe particularly useful in the treatment of prostate cancer or othercancers which are characterized by the presence of enzymatically activePSA in the immediate surrounding cancer cells, which is secreted by thecancer cells.

[0795] Compounds which are PSA conjugates and are therefore useful insuch a co-administration, and methods of synthesis thereof, can be foundin the following patents, pending patent applications and publicationswhich are herein incorporated by reference:

[0796] U.S. Pat. No. 5,599,686, granted on Feb. 4, 1997;

[0797] WO 96/00503 (Jan. 11, 1996); U.S. Ser. No. 08/404,833, filed onMar. 15, 1995;

[0798] U.S. Ser. No. 08/468,161, filed on Jun. 6, 1995;

[0799] U.S. Pat. No. 5,866,679, granted on Feb. 2, 1999;

[0800] WO 98/10651 (Mar. 19, 1998); U.S. Ser. No. 08/926,412, filed onSep. 9, 1997;

[0801] WO 98/18493 (May 7, 1998); U.S. Ser. No. 08/950,805, filed onOct. 14, 1997;

[0802] WO 99/02175 (Jan. 21, 1999); U.S. Ser. No. 09/112,656, filed onJul. 9, 1998; and

[0803] WO 99/28345 (Jun. 10, 1999); U.S. Ser. No. 09/193,365, filed onNov. 17, 1998.

[0804] Compounds which are described as prodrugs wherein the activetherapeutic agent is released by the action of enzymatically active PSAand therefore may be useful in such a co-administration, and methods ofsynthesis thereof, can be found in the following patents, pending patentapplications and publications, which are herein incorporated byreference: WO 98/52966 (Nov. 26, 1998).

[0805] All patents, publications and pending patent applicationsidentified are herein incorporated by reference.

[0806] The compounds of the instant invention are also useful as acomponent in an assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

EXAMPLES

[0807] Examples provided are intended to assist in a furtherunderstanding of the invention. Particular materials employed, speciesand conditions are intended to be further illustrative of the inventionand not limitative of the reasonable scope thereof.

Example 1 Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[11.3.1.1^(3,7)]octadeca-1(16),3(18),4,6,13(17),14-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium;2,2,2-trifluoroacetate

[0808] Step A: Preparation of 4-Bromo-3-fluorobenzoic acid

[0809] 4-Bromo-3-fluorotoluene (40.0 g, 0.212 mol) was heated at 90° C.in H₂O (200 mL)-pyridine (200 mL) with mechanical stirring under Ar.Potassium permanganate (KMnO₄) (67 g, 0.424 mol) was added portionwiseover 3 h. After 4 h, an HPLC of a filtered sample indicated 50 %conversion to the acid. An additional 30 g of KMnO₄ was added andheating continued overnight. HPLC indicated 81% conversion. FurtherKMnO₄ was added portionwise with reaction monitoring by HPLC until >95%conversion was obtained. The reaction mixture was filtered throughCelite, the filter pad washed with H₂O, aq NaOH and EtOH. The filtratewas concentrated to a small volume, then partitioned between 3N NaOHsolution and diethyl ether. The aqueous basic layer was separated,cooled in an ice-H₂O bath and acidified slowly with 6N HCl solution toprecipitate the white solid product. This was collected by suctionfiltration and dried at 40° C. in a vacuum oven overnight to give thetitle compound. mp 190-192° C.

[0810]¹H NMR (CDCl₃) δ7.83 (dd, 1H, J=2, 9 Hz), 7.78 (dd, 1H, J=2, 8Hz), 7.67-7.71 (m, 1H).

[0811] Step B: Preparation of 4-bromo-3-fluorobenzyl alcohol

[0812] 4-Bromo-3-fluorobenzoic acid (40.8 g, 0.187 mol) was dissolved inTHF (250 ml) with magnetic stirring under Ar in an ice-H₂O bath. Thecloudy solution was treated dropwise with borane-THF complex (1M) (374mL, 0.374 mol) over a 1 h period maintaining the internal temperature at<10° C. The reaction mixture was left to warm to ambient temperatureovernight, then cooled in an ice-H₂O bath and treated dropwise with H₂O(150 mL). The THF was removed on a rotary evaporator, and the residuepartitioned between EtOAc and H₂O. The aqueous layer was extracted withEtOAc (3×100 mL), the organic layers combined, washed with brine, anddried (Na₂SO₄), filtered, and concentrated to give the title compound asan oil which solidified on standing.

[0813]¹H NMR (CDCl₃) δ7.52 (t, 1H, J=8 Hz), 7.16 (d, 1H, J=9 Hz), 7.02(d, 1H, J=8 Hz), 4.67 (s, 2H), 1.47 (br s, 1H).

[0814] Step C: Preparation of 2-fluoro-4-hydroxymethylbenzonitrile

[0815] 4-Bromo-3-fluorobenzyl alcohol (20 g, 0.097 mol) was dissolved inDMF (100 mL) then placed under high vacuum for 15 min. The solution wasthen purged with Ar for 15 min. While purging continued, zinc cyanide (8g, 0.068 mol) and the catalyst, Pd[(PPh₃)]₄, (5.63 g, 0.0049 mol) wereadded. The reaction mixture was heated at 95° C. under Ar for 18 h, thencooled to ambient temperature and added to H₂O. The mixture wasextracted with EtOAc, then washed with 1M HCl, H₂O, brine, and dried(Na₂SO₄). Filtration and concentration to dryness gave the titlecompound as a white solid after chromatography (silica gel, hexane:EtOAc, 6.5:3.5).

[0816]¹H NMR (CDCl₃) δ7.61 (t, 1H, J=8 Hz), 7.23-7.29 (m, 2H), 4.80 (d,2H, J=6 Hz), 1.93 (t, 1H, J=6 Hz).

[0817] Step D: Preparation of 2-Fluoro-4-formylbenzonitrile

[0818] 2-Fluoro-4-hydroxymethylbenzonitrile (10 g, 0.066 mol) andtriethylamine (32.3 mL, 0.231 mol) were dissolved in CH₂Cl₂ (100mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with asolution of pyridineSO₃ complex (31.5 g, 0.198 mol) in DMSO (70 mL)maintaining the reaction mixture temperature at <10° C. The reactionmixture was stirred at 5° C. for 1 hr after the addition, then at 20° C.for 1 hr, then partitioned between CH₂Cl₂ and H₂O. The organic layer wasseparated, washed well with H₂O, brine, and dried (Na₂SO₄). Filtrationand concentration gave the title compound after purification bychromatography (silica gel, hexane: EtOAc, 3:1).

[0819]¹H NMR (CDCl₃) δ10.06 (d, 1H, J=2 Hz), 7.86 (dd, 1H, J=5, 8 Hz),7.798 (dd, 1H, J=1, 8 Hz), 7.728 (dd, 1H, J=1, 8 Hz).

[0820] Step E: Preparation of2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile

[0821] 1-Methylimidazole (15.88 mL, 0.199 mol), dissolved in anhydrousTHF (500 mL) in flame-dried glassware under Ar, was cooled to −78° C.and treated with n-butyl lithium (1.6M in hexane)(124 mL, 0.199 mol) viasyringe. After stirring for 1 hr chlorotriethylsilane (33.4 mL, 0.199mol) was added and the reaction mixture was left to warm to ambienttemperature overnight. The THF was removed in vacuo with gentle warming,and the residue was redissolved in dry THF (500 mL), cooled to −78° C.,and treated with sec-butyl lithium (1.3M in cyclohexane) (153 mL, 0.199mol) dropwise. After 1 hr this solution was cannulated into a solutionof 2-fluoro-4-formylbenzonitrile (27 g, 0.181 mol) in THF (200 mL).After 15 min the cooling bath was removed, the mixture was stirred for 2hr at ambient temperature, then was quenched with saturated NH₄Clsolution. After 15 min 10% HCl was added to pH 3. After 0.5 hr the THFwas removed in vacuo, the mixture was made basic with solid Na₂CO₃ andextracted with EtOAc (3×200 mL). The organics were combined, washed with10% HCl (3×), the aqueous acidic layers combined, made basic with solidNa₂CO₃, extracted with EtOAc (3×), the organics combined, washed withbrine, and dried (MgSO₄). Filtration and concentration to dryness gavethe title compound.

[0822] Step F: Preparation of2-Fluoro-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile

[0823]2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile(0.655 g, 2.83 mmol) and MnO₂ (1.23 g, 14.2 mmol) were stirred in CH₂Cl₂(50 mL) and CH₃CN (5 mL) for 3 h. The solution was filtered andconcentrated to yield the title compound.

[0824] Step G: Preparation ofN-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide

[0825] 2-Fluoro-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (2.56g, 11.2 mmol), titanium(IV) ethoxide (7.02 mL, 33.5 mmol) andcommercially available (R)-(+)-2-methyl-2-propanesulfinamide (1.35 g,11.17 mmol) were dissolved in anhydrous THF (100 mL) and heated at 75°C. for 7 days. The solution was cooled, diluted with brine (100 mL),filtered through a celite pad and washed generously with EtOAc and H₂O.The filtrate was separated, dried (MgSO₄), and purified using SiO₂chromatography (0-3% MeOH/CH₂Cl₂) to give the title compound.

[0826] Step H: Preparation of N-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-methylpropanesulfinamide

[0827]N-[(4-Cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide(1.50 g, 4.51 mmol) was dissolved in anhydrous THF (30 mL) at 0° C. andtreated with a 3.0M solution of MeMgBr (4.50 mL, 13.5 mmol) in Et₂O.After 15 min the reaction was quenched with aq. NH₄Cl solution, dilutedwith saturated NaHCO₃ solution and extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried (MgSO₄), filtered, concentrated, andrecrystallized from 95% EtOAc/Hexane to give the title compound.

[0828] Step I: Preparation of(−)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrilebishydrochloride

[0829] A cold methanolic HCl solution (50 mL) was added toN-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-methylpropanesulfinamide(0.880 g, 2.51 mmol) dissolved in MeOH (50 mL) and stirred for 1h at RT.After concentration and trituration with EtOAc the title compound wasobtained as a bis HCl salt as confirmed by chiral HPLC.

[0830] Using the procedure described above (Steps G, H, and I), butsubstituting (S)-(−)-2-methyl-2-propanesulfinamide for(R)-(+)-2-methyl-2-propanesulfinamide in Step G,(+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrilewas obtained.

[0831] Step J: Preparation ofN-[1-(4-Cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-(3-methoxy-phenyl)-propionamide

[0832](+)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrile(0.074 g, 0.25 mmol), 3-(3-methoxyphenyl)propionic acid (0.054 g, 0.3mmol) (K. J. Hwang et al., J. Org. Chem. (1992), 57[4]1262), EDC (0.275g, 1.2 mmol), HOAT (0.055 g, 0.40 mmol), and triethylamine (0.167 mL,1.2 mmol) were combined in DMF (3 mL) and stirred under Ar at ambienttemperature for 20 hr. The reaction mixture was partitioned betweenEtOAc (120 mL) and H₂O (100 mL), the organic layer separated, washedwith dilute NaHCO₃ solution, H₂O, brine, and dried (MgSO₄). Filtrationand concentration to dryness gave the title compound.

[0833] Step K: Preparation ofN-[1-(4-Cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-(3-hydroxy-phenyl)-propionamide

[0834] BBr₃ (1M in CH₂Cl₂ ) (4 mL) was added slowly to a solution ofN-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-(3-methoxy-phenyl)-propionamide(0.123 g, 0.25 mmol) in CHCl₃ (2 mL) at 0° C. After 10 min the ice bathwas removed and the mixture stirred at 20° C. for 20 min. The mixturewas cooled to 0° C., quenched with saturated NaHCO₃ solution (25 mL),then extracted with EtOAc (3×50 mL). The organic layers were combined,washed with water, brine, dried (Na₂SO₄), filtered, and concentrated togive the title compound.

[0835] FAB MS(M+1) 393

[0836] Step L: Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[11.3.1.1^(3,7)]octadeca-1(16),3(18),4,6,13(17),14-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium;2,2,2-trifluoroacetate

[0837] A solution ofN-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-(3-hydroxy-phenyl)-propionamide(0.101 g, 0.257 mmol) in DMSO (25 mL) was added dropwise to a mixture ofCs₂CO₃ (0.750 g, 0.750 mmol) in DMSO (10 mL) over a 2 hr period at 70°C. under Ar. The reaction mixture was stirred at 70° C. for 20 hr. Thecooled mixture was partitioned between EtOAc (120 mL) and H₂O (120 mL),the aqueous layer washed with EtOAc, the organics combined, washed withH₂O, brine, and dried (Na₂SO₄). Filtration and concentration to drynessgave the title compound after preparative RPLC on a Gilson preparativeLC.

[0838] HRMS theoretical: 373.1659; measured: 373.1656.

Example 2 Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3(20),4,6,15(19),16-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium;2,2,2-trifluoroacetate

[0839] Step A: Preparation of 3-(3-Methoxyphenyl)propanol

[0840] 3-(3-Methoxyphenyl)propionic acid (see Example 1, Step J) (10.09g, 0.058 mol) dissolved in anhydrous THF 60 mL) was added dropwise to asolution of LiAlH₄ (1M in THF) (60 mL, 0.06 mol) in THF (60 mL) atambient temperature under Ar. The resulting solution was stirred atreflux for 6 hr, then cooled to 0° C., treated dropwise with H₂O (2.2mL), 20% NaOH (1.7 mL), then H₂O (6.62 mL). After stirring for 15 min,MgSO₄ was added, stirring was continued for 15 min, the solids werefiltered off, washed well with EtOAc, and the filtrate concentrated todryness to give the title compound. MS (M+1) 167.1

[0841] Step B: Preparation of 3-(3-Methoxyphenyl)propylbromide

[0842] Allyl bromide (25 mL, 0.28 mmol) was added to a solution of3-(3-methoxyphenyl)propanol (8.8 g, 0.053 mol), N,N′-carbonyldiimidazole(9.6 g, 0.0605 mol) and CH₃CN (45 mL) at room temperature. After 1.5 hrat rt and 1.5 hr at reflux, the reaction mixture was cooled, partitionedbetween EtOAc (250 mL) and H₂O (300 mL), the organic layer washed withH₂O (300mL), 5% HCl (200 mL), dilute NaHCO₃ solution (200 mL), brine(300 mL), and dried (Na₂SO₄). Filtration and concentration to drynessgave the title compound.

[0843] Step C: Preparation of 2-[3-(3-Methoxy-phenyl)-propyl]-malonicacid diethyl ester

[0844] Diethylmalonate (7.65 mL, 0.050 mol) was added slowly to avigorously stirred suspension of pre-washed NaH (60%) (2.4 g, 0.050 mol)in dry DMF (50 mL) at 0° C. under Ar. After 15 min,3-(3-methoxyphenyl)propylbromide (11.5 g, 0.050 mol) was added slowly,the ice bath was removed, and the reaction mixture was stirred at 65° C.for 16 hr. The mixture was cooled, partitioned between EtOAc (250 mL)and H₂O (200 mL), the organic layer washed with H₂O (2×500 mL), dried(Na₂SO₄), filtered, and concentrated to dryness to give the titlecompound.

[0845] FAB MS(M+1) 309.1

[0846] Step D: Preparation of 5-(3-Methoxyphenyl)pentanoic acid

[0847] KOH (7.0 g, 0.105 mol) was added slowly to a hot solution of thediester from Step C (14 g, 0.046 mol) in ethylene glycol (50 mL) withstirring under Ar. The reaction mixture was heated at reflux for 3 hr,cooled, acidified to pH=2 with HCl, diluted with H₂O (150 mL), andextracted with benzene (3×50 mL). The organic layers were combined,washed with dilute NaHCO₃ solution (2×100 mL), H₂O (2×50 mL), dried,filtered, and concentrated to dryness to give the title compound afterchromatography on SiO₂ eluting with CHCl₃:MeOH, 40:1.

[0848] HRMS: theoretical, 226.1438; measured, 226.1435.

[0849] Step E: Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[13.3.1.1^(3,7)eicosa-1(18),3(20),4,6,15(19),16-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium; 2,2,2-trifluoroacetate

[0850] Following the procedures described in Example 1, Steps J, K and Lbut substituting 5-(3-methoxyphenyl)pentanoic acid for3-(3-methoxyphenyl)propionic acid, the title compound was prepared.

[0851] HRMS: theoretical, 401.1972; measured, 401.1951.

Example 3 Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium;2,2,2-trifluoroacetate

[0852] Using the procedures described in Example 2, but substituting5-(3-methoxyphenyl)pentanoic acid (Example 2, Step D) for5-(3-methoxyphenyl) propionic acid in Step A, the title compound wasprepared.

[0853] HRMS: theoretical, 429.2285; measured, 429.2283.

Example 4 Preparation of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-(16-spiro-(2-cyclohexanone)tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate

[0854]

[0855] Step A: Preparation of5-[1-(3-Methoxy-phenyl)-2-oxo-cyclohexyl]-pentanoic acid ethyl ester

[0856] 2-(3-Methoxy-phenyl)-cyclohexanone (0.80 g, 4.05 mmol) was addedslowly to a suspension of NaH (60%) (0.185 g, 5.1 mmol) in anhydrous DMF(5 mL) at 0° C. under Ar over 15 min. After an additional 15 min. at 20°C. 6-bromohexanoic acid ethyl ester (1.0 g, 4.5 mmol) was added followedby stirring at 60° C. for 6 hr. The reaction mixture was cooled,quenched with saturated NH₄Cl solution, partitioned between EtOAc (150mL) and H₂O (100 mL), the organic layer washed with H₂O (2×100 mL),dried (Na₂SO₄), filtered, and concentrated to dryness to give the titlecompound after silica gel chromatography eluting with hexane:EtOAc, 50:1to 10:1.

[0857] Step B: Preparation of5-[1-(3-Methoxy-phenyl)-2-oxo-cyclohexyl]-pentanoic acid

[0858] Solid KOH (0.090 g, 1.4 mmol) was added to a solution of theester from Step A (0.132 g, 0.38 mmol) in EtOH (5 mL). After stirring atambient temperature for 48 hr, the reaction mixture was partitionedbetween EtOAc (50 mL) and H₂O (100 mL), the aqueous layer acidified,then extracted with EtOAc (2×100 mL), the organic layer washed with H₂O(50 mL), dried (Na₂SO₄), filtered, and concentrated to dryness to givethe title compound. Mp 89-91° C. MS 318.

[0859] Step C: Preparation of 5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-16-spiro(2-cyclohexanone)tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium;2,2,2-trifluoroacetate

[0860] Using the procedures described in Example 1, Steps J, K and L,but substituting 5-[1-(3-methoxy-phenyl)-2-oxo-cyclohexyl]-pentanoicacid from Step B above for 3-(3-methoxyphenyl) propionic acid in Step J,the title compound was prepared.

[0861] HRMS: theoretical, 511.2704; measured, 511.2692.

[0862] The other enantiomer of5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-16-spiro (2-cyclohexanone)tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium; 2,2,2-trifluoroacetate was prepared using(−)-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-fluoro-benzonitrilebishydrochloride from Example 1, Step I.

[0863] HRMS: theoretical, 511.2704; measured, 511.2701.

Example 5 Preparation of14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclor13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

[0864] Step A: Preparation of 3-tert-butoxy-benzoic acid ethyl esterInto a solution of 3-hydroxy-benzoic acid ethyl ester (10.14 g, 0.061mol) in CH₂Cl₂ (200 mL) cooled to −78° C. was condensed isobutylene (150mL) followed by addition of triflic acid (1.08 mL, 0.061 mol). Thereaction mixture was allowed to warm to −20° C. When a solution wasobtained and tlc indicated loss of starting material, the reaction wasquenched with Et₃N (6.8 mL, 0.049 mol) and left to warm to ambienttemperature. The solution was concentrated and the residuechromatographed on an ISCO combiflash eluting with 0-10% EtoAc/hexane togive 12.91 g (95%) of the title compound.

[0865]¹H NMR (CDCl₃) δ7.76 (d, 1H, J=8 Hz), 7.66 (s, 1H), 7.33 (t, 1H,J=8 Hz), 7.26 (s, 1H), 7.18 (dd, 1H, J=2, 8 Hz), 4.37 (q, 2H, J=7 Hz),1.39 (t, 3H, J=7 Hz, 1.37 (s, 9H).

[0866] Step B: Preparation of (3-tert-butoxy-phenyl) methanol

[0867] To a suspension of LiAlH₄ (1.707 g, 0.045 mol) in anhydrousdiethyl ether (80 mL) in a 3-necked rb flask equipped with additionfunnel at 0° C. in an ice-water bath was added dropwise a solution of3-tert-butoxy-benzoic acid ethyl ester (5.0 g, 0.0225 mol) in ether (20mL). The reaction mixture was left to warm to rt over 15 min, thencooled in an ice-water bath and quenched by dropwise addition of H₂O.The mixture was partitioned between ether and H₂O, the aqueous layerwashed with ether (2×30 mL), the organics combined, washed with brine,dried (MgSO₄), filtered and concentrated to give 3.70 g (82%) of thetitle compound.

[0868]¹H NMR (CDCl₃) δ7.23-7.27 (m, 1H), 7.07 (d, 1H, J=8 Hz), 7.00 (s,1H), 6.92 (d, 3H, J=8 Hz), 4.66 (d, 2H, J=5 Hz), 1.69 (t, 1H, J=5 Hz),1.35 (s, 9H).

[0869] Step C: Preparation of1-(4-bromo-butoxymethyl)-3-tert-butoxy-benzene

[0870] To a solution of (3-tert-butoxy-phenyl) methanol (4.02 g, 0.022mol) and tetrabutylammonium hydrogen sulfate (0.379 g, 0.00115 mol) in50% NaOH solution (6 mL) and benzene (15 mL) Was added 1,4-dibromobutane(7.99 mL, 0.067 mol) with vigorous stirring at ambient temperature.After stirring for 8 h, the mixture was partitioned between H₂O andEtOAc. The organic layer was separated, washed with brine, dried(MgSO₄), filtered, and concentrated to give the title compound afterpurification on an ISCO Combiflash eluting with 0-10% EtOAc/hexane.

[0871]¹H NMR (CDCl₃) δ7.23 (t, 1H, J=8 Hz), 7.03 (d, 1H, J=8 Hz), 6.96(s, 1H), 6.91 (dd, 1H, J=1, 8 Hz), 4.47 (s, 2H), 3.48 (t, 1H, J=6 Hz),3.43 (t, 1H, J=6 Hz), 1.94-2.01 (m, 2H), 1.72 -1.79 (m, 2H), 1.35 (s,9H).

[0872] Step D: Preparation of 2-methyl-propane-2-sulfinic acid[5-(3-tert-butoxy-benzyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-amide

[0873] Magnesium (0.09 g, 3.61 mmol) was flame dried in a 50 mL RB flaskequipped with addition funnel and magnetic stirrer under N₂. When theflask had cooled, anhydrous THF (3 mL), a pinch of iodine, and a THFsolution of Rieke magnesium (1 mL) were added, followed by a smallportion of 1-(4-bromo-butoxymethyl)-3-tert-butoxy-benzene (1.134 g, 3.61mmol) in THF (5 mL) with slight warming to initiate the reaction. Theremainder of the bromide solution was added dropwise over 15 min. After15 min. this Grignard solution was added to a solution ofN-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide(Example 1, Step G) (0.30 g, 0.90 mmol) in THF (5 mL) with cooling in anice-H₂O bath. After 5 mL of Grignard solution was consumed, the reactionwas complete by HPLC. The reaction mixture was quenched with H₂O,diluted with saturated NaHCO₃ solution and extracted with CH₂Cl₂ (2×20mL). The organic layers were combined, washed with brine, dried (MgSO₄),filtered and concentrated to give the crude product. Purification by RPLC on a Delta Prep Pak eluting with 95:5 to 5:95 H₂O (0.1% TFA):CH₃CN(0.1% TFA) gave both diastereomers in a 3.5:1 ratio afterconcentration of the fractions followed by a toluene azeotrope. MS (M+1)569 for both diastereomers A and B.

[0874] Step E: Preparation of4-[1-amino-5-(3-hydroxy-benzyloxy)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-2-fluoro-benzonitrile

[0875] 2-Methyl-propane-2-sulfinic acid[5-(3-tert-butoxy-benzyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-amide(A) (0.396 g, 0.58 mmol) was dissolved in methanol (15 mL) and treatedwith 4M HCl in dioxane (9 mL). After 1 h, the reaction mixture wasconcentrated in vacuo, azeotroped with CH₂Cl₂ (3×), rinsed with CH₂Cl₂,and the solid collected to give enantiomer A of the title compound. MS(M+1) 409. Using the same procedure, diastereomer B (Step D) (0.110 g,0.161 mmol) gave enantiomer B of the title compound.

[0876] Step F: Preparation of14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

[0877]4-[1-Amino-5-(3-hydroxy-benzyloxy)-1-(3-methyl-3H-imidazol-4-yl)-pentyl]-2-fluoro-benzonitrile(0.214 g, 0.443 mmol) was dissolved in DMF (44 mL) at ambienttemperature and treated with Cs₂CO₃ (0.577 g, 1.77 mmol). After 18 h,the reaction mixture was concentrated to dryness, and partitionedbetween a minimum amount of H₂O and CH₂Cl₂. The aqueous layer was washedwith CH₂Cl₂ (2×), the organics combined, dried (MgSO₄), filtered andconcentrated to give the title compound after purification on the ISCOCombiflash eluting with 1-3% MeOH/CH₂Cl₂w/ NH₄OH. MS (M+1) 389.

[0878] Anal. Calculated for C₂₃H₂₄N₄O₂.0.3 H₂0: C, 70.14; H, 6.30; N,14.22; Found: C, 70.04; H, 6.29; N, 13.97.

[0879] Using the same procedure but substituting enantiomer B from StepE, the other enantiomer of14-amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrilewas prepared. MS (M+1) 389.

[0880] Anal. Calculated for C₂₃H₂₄N₄O₂.0.1 H₂O: C, 70.78; H, 6.25; N,14.36; Found: C, 70.62; H, 6.31; N, 14.49.

Example 6 Preparation of15-Amino-15-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[14.3.1.1^(3,7)]heneicosa-1(20),3,5,7(21),16.18-hexaene-19-carbonitrile

[0881] Using the procedures described in Example 5, but substituting1,5-dibromopentane for 1,4-dibromobutane in Step C, the title compoundwas prepared.

[0882] MS (M+1) 403.

Example 7 Preparation of14-amino-14-(3-methyl-3H-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

[0883] Step A: Preparation of 2-methyl-propane-2-sulfinic acid[4-tert-butyl-dimethyl-silanyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-butyl]-amide

[0884] Magnesium (0.317 g, 12.03 mmol) was flame dried in a 50 mL RBflask equipped with addition funnel and magnetic stirrer under N₂. Whenthe flask had cooled, anhydrous THF (3 mL), a pinch of iodine, and a THFsolution of Rieke magnesium (1 mL) were added, followed by a smallportion of (3-bromopropoxy)-tert-butyldimethylsilane (3.048 g, 12.03mmol) in THF (5 mL) with slight warming to initiate the reaction. Theremainder of the bromide solution was added dropwise over 15 min. After15 min. this Grignard solution was added to a solution ofN-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide(Example 1, Step G) (1.00 g, 3.01 mmol) in THF (5 mL) with cooling in anice-H₂O bath. After 5 mL of Grignard solution was consumed, the reactionwas complete by HPLC. The reaction mixture was quenched with H₂O,diluted with saturated NaHCO₃ solution and extracted with CH₂Cl₂ (2×20mL). The organic layers were combined, washed with brine, dried (MgSO₄),filtered and concentrated to give the crude product. Purification on anISCO Combiflash eluting with 1-3% MeOH/CH₂Cl₂ w/ NH₄OH gave the titlecompound.

[0885] Step B: Preparation of 2-methyl-propane-2-sulfinic acid[4-hydroxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-butyl]-amide

[0886] 2-Methyl-propane-2-sulfinic acid[4-tert-butyl-dimethyl-silanyloxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-butyl]-amide(0.84 g, 1.66 mmol) was dissolved in THF (15 mL), treated withtetrabutylammonium fluoride and stirred at ambient temperature for 0.5h. The mixture was partitioned between CH₂Cl₂ and aqueous saturatedNaHCO₃ solution, the aqueous layer washed with CH₂Cl₂ (3×20 mL), theorganic layers combined, washed with brine and dried (MgSO₄). Filtrationand concentration gave the title compound after chromatography on anISCO Combiflash eluting with 2-6% MeOH/CH₂Cl₂ w/ NH₄OH. MS (M+1) 393.

[0887] Step C: Preparation of 2-methyl-propane-2-sulfinic acid[1-(4-cyano-3-fluoro-phenyl)-4-[2-(3-methoxy-phenyl)-ethylamino]-1-(3-methyl-3-H-imidazol-4-yl)-butyl]-amide

[0888] 2-Methyl-propane-2-sulfinic acid[4-hydroxy)-1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-butyl]-amide(0.025 g, 0.0637 mmol) was dissolved in anhydrous CH₂Cl₂ (3 mL) atambient temperature, then treated with the Dess-Martin periodate (0.058mL, 0.596 mmol). After 0.5 h, the reaction mixture was partitionedbetween CH₂Cl₂ and saturated NaHCO₃ solution, the aqueous layerseparated, washed with CH₂Cl₂ (3×), the organics combined and dried(MgSO₄). Filtration and concentration gave crude aldehyde that wasdissolved in MeOH (5 mL). 3-Methoxy-phenethylamine (0.0093 mL, 0.0637mmol) was added, the pH adjusted to 5 with acetic acid, then NaCNBH₃(0.006 g, 0.0956 mmol) added, and the mixture was stirred at for 18 h.The crude product was purified by RP LC on a Delta PrepPak eluting with95:5 to 5:95 H₂O (0.1% TFA): CH₃CN(0.1% TFA) to give the title compound.MS (M+1) 526.

[0889] Step D: Preparation of4-[1-amino-4-[2-(3-hydroxy-phenyl)-ethylamino]-1-(3-methyl-3H-imidazol-4-yl)-butyl]-2-fluoro-benzonitrile

[0890] 2-Methyl-propane-2-sulfinic acid[1-(4-cyano-3-fluoro-phenyl)-4-[2-(3-methoxy-phenyl)-ethylamino]-1-(3-methyl-3-H-imidazol-4-yl)-butyl]-amide(0.075 g, 0.1427 mmol) was dissolved in CH₂Cl₂ (7 mL) with cooling in anice-H₂O bath, then treated with BBr₃ (1 mL of a 1M solution in CH₂Cl₂, 1mmol). After 15 min., H₂O (3 mL) was added and the reaction mixture wasconcentrated in vacuo. The residue was dissolved in MeOH and stirred atambient temperature for 15 min. Concentration to dryness gave the titlecompound which was used without further purification. MS (M+1) 408.

[0891] Step E: Preparation of14-amino-14-(3-methyl-3H-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

[0892]4-[1-Amino-4-[2-(3-hydroxy-phenyl)-ethylamino]-1-(3-methyl-3H-imidazol-4-yl)-butyl]-2-fluoro-benzonitrile(0.058 g, 0.142 mmol) was dissolved in DMF (15 mL) and treated withCs₂CO₃ (0.324 g, 0.994 mmol). After 18 h at 60° C., the reaction mixturewas concentrated in vacuo, dissolved in H₂O: 0.1% TFA (3 mL) andpurified by RP LC on a Delta PrepPak eluting with 95:5 to 5:95 H₂O (0.1%TFA): CH₃CN(0.1% TFA) to give the title compound as an 80:20 mixture ofenantiomers.

[0893] MS (M+1) 388.

Example 8

[0894] In vitro inhibition of ras farnesyl transferase

[0895] Transferase Assays. Isoprenyl-protein transferase activity assaysare carried out at 30° C. unless noted otherwise. A typical reactioncontains (in a final volume of 50 μL): [³H]farnesyl diphosphate, Rasprotein, 50 mM HEPES, pH 7.5, 5 mM MgCl₂, 5 mM dithiothreitol, 10 μMZnCl₂, 0.1% polyethyleneglycol (PEG) (15,000-20,000 mw) andisoprenyl-protein transferase. The FPTase employed in the assay isprepared by recombinant expression as described in Omer, C. A., Kral, A.M., Diehl, R. E., Prendergast, G. C., Powers, S., Allen, C. M., Gibbs,J. B. and Kohl, N. E. (1993) Biochemistry 32:5167-5176. After thermallypre-equilibrating the assay mixture in the absence of enzyme, reactionsare initiated by the addition of isoprenyl-protein transferase andstopped at timed intervals (typically 15 min) by the addition of 1M HClin ethanol (1 mL). The quenched reactions are allowed to stand for 15 m(to complete the precipitation process). After adding 2 mL of 100%ethanol, the reactions are vacuum-filtered through Whatman GF/C filters.Filters are washed four times with 2 mL aliquots of 100% ethanol, mixedwith scintillation fluid (10 mL) and then counted in a Beckman LS3801scintillation counter.

[0896] For inhibition studies, assays are run as described above, exceptinhibitors are prepared as concentrated solutions in 100% dimethylsulfoxide and then diluted 20-fold into the enzyme assay mixture.Substrate concentrations for inhibitor IC₅₀ determinations are asfollows: FTase, 650 nM Ras-CVLS (SEQ.ID.NO.: 1), 100 nM farnesyldiphosphate.

[0897] The compounds of the instant invention are tested for inhibitoryactivity against human FPTase by the assay described above.

[0898] The compounds of the instant invention described in the aboveExamples 1-7 were tested for inhibitory activity against human FPTase bythe assay described above and were found to have an IC₅₀ of ≦5 μM.

Example 9

[0899] Modified In vitro GGTase inhibition assay

[0900] The modified geranylgeranyl-protein transferase inhibition assayis carried out at room temperature. A typical reaction contains (in afinal volume of 50 μL): [³H]geranylgeranyl diphosphate, biotinylated Raspeptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mMglycerophosphate or 5mM ATP), 5 mM MgCl₂, 10 μM ZnCl₂, 0.1% PEG(15,000-20,000 mw), 2 mM dithiothreitol, and geranylgeranyl-proteintransferase type I(GGTase). The GGTase-type I enzyme employed in theassay is prepared as described in U.S. Pat. No. 5,470,832, incorporatedby reference. The Ras peptide is derived from the K4B-Ras protein andhas the following sequence: biotinyl-GKKKKKKSKTKCVIM (single amino acidcode) (SEQ.ID.NO.: 2). Reactions are initiated by the addition of GGTaseand stopped at timed intervals (typically 15 min) by the addition of 200μL of a 3 mg/mL suspension of streptavidin SPA beads (ScintillationProximity Assay beads, Amersham) in 0.2M sodium phosphate, pH 4,containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowedto stand for 2 hours before analysis on a Packard TopCount scintillationcounter.

[0901] For inhibition studies, assays are run as described above, exceptinhibitors are prepared as concentrated solutions in 100% dimethylsulfoxide and then diluted 25-fold into the enzyme assay mixture. IC₅₀values are determined with Ras peptide near KM concentrations. Enzymeand substrate concentrations for inhibitor IC₅₀ determinations are asfollows: 75 pM GGTase-I, 1.6 μM Ras peptide, 100 nM geranylgeranyldiphosphate.

[0902] The compounds of the instant invention are tested for inhibitoryactivity against human GGTase-type I by the assay described above.

Example 10

[0903] Cell-based in vitro ras farnesylation assay

[0904] The cell line used in this assay is a v-ras line derived fromeither Rat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assayis performed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labeled in 3 ml methionine-free DMEM supplemented with 10%regular DMEM, 2% fetal bovine serum and 400 pCi[³⁵S]methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂/1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) andimmuno-precipitated with the ras-specific monoclonal antibody Y13-259(Furth, M. E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hourantibody incubation at 4° C., 200 μl of a 25% suspension of proteinA-Sepharose coated with rabbit anti rat IgG is added for 45 min. Theimmuno-precipitates are washed four times with IP buffer (20 nM HEPES,pH 7.5/1 mM EDTA/1% Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCl)boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. Whenthe dye front reached the bottom, the gel is fixed, soaked inEnlightening, dried and autoradiographed. The intensities of the bandscorresponding to farnesylated and nonfarnesylated ras proteins arecompared to determine the percent inhibition of farnesyl transfer toprotein.

Example 11

[0905] Cell-based in vitro growth inhibition assay

[0906] To determine the biological consequences of FPTase inhibition,the effect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

[0907] Rat 1 cells transformed with either v-ras, v-raf, or v-mos areseeded at a density of 1×10⁴ cells per plate (35 mm in diameter) in a0.3% top agarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

Example 12

[0908] Construction of SEAP reporter plasmid pDSE 100

[0909] The SEAP reporter plasmid, pDSE100 was constructed by ligating arestriction fragment containing the SEAP coding sequence into theplasmid pCMV-RE-AKI. The SEAP gene is derived from the plasmidpSEAP2-Basic (Clontech, Palo Alto, Calif.). The plasmid pCMV-RE-AKI wasconstructed by Deborah Jones (Merck) and contains 5 sequential copies ofthe ‘dyad symmetry response element’ cloned upstream of a ‘CAT-TATA’sequence derived from the cytomegalovirus immediate early promoter. Theplasmid also contains a bovine growth hormone poly-A sequence.

[0910] The plasmid, pDSE100 was constructed as follows. A restrictionfragment encoding the SEAP coding sequence was cut out of the plasmidpSEAP2-Basic using the restriction enzymes EcoRl and HpaI. The ends ofthe linear DNA fragments were filled in with the Klenow fragment of E.coli DNA Polymerase I. The ‘blunt ended’ DNA containing the SEAP genewas isolated by electrophoresing the digest in an agarose gel andcutting out the 1694 base pair fragment. The vector plasmid pCMV-RE-AKIwas linearized with the restriction enzyme Bgl-II and the ends filled inwith Klenow DNA Polymerase I. The SEAP DNA fragment was blunt endligated into the pCMV-RE-AKI vector and the ligation products weretransformed into DH5-alpha E. coli cells (Gibco-BRL). Transformants werescreened for the proper insert and then mapped for restriction fragmentorientation. Properly oriented recombinant constructs were sequencedacross the cloning junctions to verify the correct sequence. Theresulting plasmid contains the SEAP coding sequence downstream of theDSE and CAT-TATA promoter elements and upstream of the BGH poly-Asequence.

[0911] Alternative Construction of SEAP reporter plasmid, pDSE101

[0912] The SEAP repotrer plasmid, pDSE101 is also constructed byligating a restriction fragment containing the SEAP coding sequence intothe plasmid pCMV-RE-AKI. The SEAP gene is derived from plasmidpGEM7zf(−)/SEAP.

[0913] The plasmid pDSE101 was constructed as follows: A restrictionfragment containing part of the SEAP gene coding sequence was cut out ofthe plasmid pGEM7zf(−)/SEAP using the restriction enzymes Apa I andKpnI. The ends of the linear DNA fragments were chewed back with theKlenow fragment of E. coli DNA Polymerase I. The “blunt ended” DNAcontaining the truncated SEAP gene was isolated by electrophoresing thedigest in an agarose gel and cutting out the 1910 base pair fragment.This 1910 base pair fragment was ligated into the plasmid pCMV-RE-AKIwhich had been cut with Bgl-II and filled in with E. coli Klenowfragment DNA polymerase. Recombinant plasmids were screened for insertorientation and sequenced through the ligated junctions. The plasmidpCMV-RE-AKI is derived from plasmid pCMVIE-AKI-DHFR (Whang, Y.,Silberklang, M., Morgan, A., Munshi, S., Lenny, A. B., Ellis, R. W., andKieff, E. (1987) J. Virol., 61, 1796-1807) by removing an EcoRI fragmentcontaining the DHFR and Neomycin markers. Five copies of the fospromoter serum response element were inserted as described previously(Jones, R. E., Defeo-Jones, D., McAvoy, E. M., Vuocolo, G. A., Wegrzyn,R. J., Haskell, K. M. and Oliff, A. (1991) Oncogene, 6, 745-751) tocreate plasmid pCMV-RE-AKI.

[0914] The plasmid pGEM7zf(−)/SEAP was constructed as follows. The SEAPgene was PCRed, in two segments from a human placenta cDNA library(Clontech) using the following oligos. Sense strand 5′GAGAGGGAATTCGGGCCCTTCCTGCATGCTGCTGCTGCTGCTGCTGCTGGGC 3′ (SEQ.ID.NO.:4)N-terminal SEAP: Antisense strand 5′GAGAGAGCTCGAGGTTAACCCGGGTGCGCGGCGTCGGTGGT 3′ (SEQ.ID.NO.:5) N-terminalSEAP: Sense strand 5′ GAGAGAGTCTAGAGTTAACCCGTGGTCCCCGCGTTGCTTCCT 3′(SEQ.ID.NO.:6) C-terminal SEAP: Antisense strand 5′GAAGAGGAAGCTTGGTACCGCCACTGGGCTGTAGGTGGTGGCT 3′ (SEQ.ID.NO.:7) C-terminalSEAP:

[0915] The N-terminal oligos (SEQ.ID.NO.: 4 and SEQ.ID.NO.: 5) were usedto generate a 1560 bp N-terminal PCR product that contained EcoRI andHpaI restriction sites at the ends. The Antisense N-terminal oligo(SEQ.ID.NO.: 5) introduces an internal translation STOP codon within theSEAP gene along with the HpaI site. The C-terminal oligos (SEQ.ID.NO.: 6and SEQ.ID.NO.: 7) were used to amplify a 412 bp C-terminal PCR productcontaining HpaI and HindIII restriction sites. The sense strandC-terminal oligo (SEQ.ID.NO.: 6) introduces the internal STOP codon aswell as the HpaI site. Next, the N-terminal amplicon was digested withEcoRI and HpaI while the C-terminal amplicon was digested with HpaI andHindIII. The two fragments comprising each end of the SEAP gene wereisolated by electro-phoresing the digest in an agarose gel and isolatingthe 1560 and 412 base pair fragments. These two fragments were thenco-ligated into the vector pGEM7zf(−) (Promega) which had beenrestriction digested with EcoRI and HindIII and isolated on an agarosegel. The resulting clone, pGEM7zf(−)/SEAP contains the coding sequencefor the SEAP gene from amino acids.

[0916] Construction of a constitutively expressing SEAP plasmidPCMV-SEAP-A

[0917] An expression plasmid constitutively expressing the SEAP proteinwas created by placing the sequence encoding a truncated SEAP genedownstream of the cytomegalovirus (CMV) IE-1 promoter. The expressionplasmid also includes the CMV intron A region 5′ to the SEAP gene aswell as the 3′ untranslated region of the bovine growth hormone gene 3′to the SEAP gene.

[0918] The plasmid pCMVIE-AKI-DHFR (Whang, Y., Silberklang, M., Morgan,A., Munshi, S., Lenny, A. B., Ellis, R. W., and Kieff, E. (1987) J.Virol., 61:1796-1807) containing the CMV immediate early promoter wascut with EcoRI generating two fragments. The vector fragment wasisolated by agarose electrophoresis and religated. The resulting plasmidis named pCMV-AKI. Next, the cytomegalovirus intron A nucleotidesequence was inserted downstream of the CMV IE1 promter in pCMV-AKI. Theintron A sequence was isolated from a genomic clone bank and subclonedinto pBR322 to generate plasmid p16T-286. The intron A sequence wasmutated at nucleotide 1856 (nucleotide numbering as in Chapman, B. S.,Thayer, R. M., Vincent, K. A. and Haigwood, N. L., Nuc. Acids Res. 19,3979-3986) to remove a SacI restriction site using site directedmutagenesis. The mutated intron A sequence was PCRed from the plasmidp16T-287 using the following oligos. Sense strand: 5′GGCAGAGCTCGTTTAGTGAACCGTCAG 3′ (SEQ.ID.NO.:8) Antisense strand: 5′GAGAGATCTCAAGGACGGTGACTGCAG 3′ (SEQ.ID.NO.:9)

[0919] These two oligos generate a 991 base pair fragment with a SacIsite incorporated by the sense oligo and a Bgl-II fragment incorporatedby the antisense oligo. The PCR fragment is trimmed with SacI and Bgl-IIand isolated on an agarose gel. The vector pCMV-AKI is cut with SacI andBgl-II and the larger vector fragment isolated by agarose gelelectrophoresis. The two gel isolated fragments are ligated at theirrespective SacI and Bgl-II sites to create plasmid pCMV-AKI-InA.

[0920] The DNA sequence encoding the truncated SEAP gene is insertedinto the pCMV-AKI-InA plasmid at the Bgl-II site of the vector. The SEAPgene is cut out of plasmid pGEM7zf(−)/SEAP (described above) using EcoRIand HindIII. The fragment is filled in with Klenow DNA polymerase andthe 1970 base pair fragment isolated from the vector fragment by agarosegel electrophoresis. The pCMV-AKI-InA vector is prepared by digestingwith Bgl-II and filling in the ends with Klenow DNA polymerase. Thefinal construct is generated by blunt end ligating the SEAP fragmentinto the pCMV-AKI-InA vector. Transformants were screened for the properinsert and then mapped for restriction fragment orientation. Properlyoriented recombinant constructs were sequenced across the cloningjunctions to verify the correct sequence. The resulting plasmid, namedpCMV-SEAP-A (deposited in the ATCC under Budapest Treaty on Aug. 27,1998, and designated ATCC), contains a modified SEAP sequence downstreamof the cytomegalovirus immediately early promoter IE-1 and intron Asequence and upstream of the bovine growth hormone poly-A sequence. Theplasmid expresses SEAP in a constitutive manner when transfected intomammalian cells.

[0921] Alternative construction of a constitutively expressing SEAPplasmid pCMV-SEAP-B

[0922] An expression plasmid constitutively expressing the SEAP proteincan be created by placing the sequence encoding a truncated SEAP genedownstream of the cytomegalovirus (CMV) IE-I promoter and upstream ofthe 3′ unstranslated region of the bovine growth hormone gene.

[0923] The plasmid pCMVIE-AKI-DHFR (Whang, Y., Silberklang, M., Morgan,A., Munshi, S., Lenny, A. B., Ellis, R. W., and Kieff, E. (1987) J.Virol., 61:1796-1807) containing the CMV immediate early promoter andbovine growth hormone poly-A sequence can be cut with EcoRI generatingtwo fragments. The vector fragment can be isolated by agaroseelectrophoresis and religated. The resulting plasmid is named pCMV-AKI.The DNA sequence encoding the truncated SEAP gene can be inserted intothe pCMV-AKI plasmid at a unique Bgl-II in the vector. The SEAP gene iscut out of plasmid pGEMzf(−)/SEAP (described above) using EcoRI andHindIII. The fragments are filled in with Klenow DNA polymerase and the1970 base pair fragment is isolated from the vector fragment by agarosegel electrophoresis. The pCMV-AKI vector is prepared by digesting withBgl-II and filling in the ends with Klenow DNA polymerase. The finalconstruct is generated by blunt end ligating the SEAP fragment into thevector and transforming the ligation reaction into E. coli DH5α cells.Transformants can then be screened for the proper insert and mapped forrestriction fragment orientation. Properly oriented recombinantconstructs would be sequenced across the cloning junctions to verify thecorrect sequence. The resulting plasmid, named pCMV-SEAP-B contains amodified SEAP sequence downstream of the cytomegalovirus immediate earlypromoter, IE1, and upstream of a bovine growth hormone poly-A sequence.The plasmid would express SEAP in a constitutive nammer when transfectedinto mammalian cells.

[0924] Cloning of a Myristylated viral-H-ras expression plasmid pSMS600

[0925] A DNA fragment containing viral-H-ras can be PCRed from plasmid“HB-11” (deposited in the ATCC under Budapest Treaty on Aug. 27, 1997,and designated ATCC 209,218) using the following oligos. Sense strand:5′TCTCCTCGAGGCCACCATGGGGAGTAGCAAGAGCAAGCCTAAGGACCC (SEQ.ID.NO.:10)CAGCCAGCGCCGGATGACAGAATACAAGCTTGTGGTGG3′.

[0926] Antisense: 5′CACATCTAGATCAGGACAGCACAGACTTGCAGC3′. (SEQ.ID.NO.:11)

[0927] A sequence encoding the first 15 aminoacids of the v-src gene,containing a myristylation site, is incorporated into the sense strandoligo. The sense strand oligo also optimizes the ‘Kozak’ translationinitiation sequence immediately 5′ to the ATG start site. To preventprenylation at the viral-ras C-terminus, cysteine 186 would be mutatedto a serine by substituting a G residue for a C residue in theC-terminal antisense oligo. The PCR primer oligos introduce an XhoI siteat the 5′ end and a XbaI site at the 3′end. The XhoI-XbaI fragment canbe ligated into the mammalian expression plasmid pCI (Promega) cut withXhoI and XbaI. This results in a plasmid, pSMS600, in which therecombinant myr-viral-H-ras gene is constitutively transcribed from theCMV promoter of the pCI vector.

[0928] Cloning of a viral-H-ras-CVLL expression plasmid pSMS601

[0929] A viral-H-ras clone with a C-terminal sequence encoding the aminoacids CVLL can be cloned from the plasmid “HB-11” by PCR using thefollowing oligos. Sense strand:5′TCTCCTCGAGGCCACCATGACAGAATACAAGCTTGTGGTGG-3′ (SEQ.ID.NO.:12)

[0930] Antisense strand: 5′CACTCTAGACTGGTGTCAGAGCAGCACACACTTGCAGC-3′(SEQ.ID.NO.:13)

[0931] The sense strand oligo optimizes the ‘Kozak’ sequence and adds anXhoI site. The antisense strand mutates serine 189 to leucine and addsan XbaI site. The PCR fragment can be trimmed with XhoI and XbaI andligated into the XhoI-XbaI cut vector pCI (Promega). This results in aplasmid, pSMS601, in which the mutated viral-H-ras-CVLL gene isconstitutively transcribed from the CMV promoter of the pCI vector.

[0932] Cloning of cellular-H-ras-Leu61 expression plasmid pSMS620

[0933] The human cellular-H-ras gene can be PCRed from a human cerebralcortex cDNA library (Clontech) using the following oligonucleotideprimers. Sense strand 5′-GAGAGAATTCGCCACCATGACGGAATATAAGCTGGTGG-3′(SEQ.ID.NO.:14)

[0934] Antisense strand: 5′-GAGAGTCGACGCGTCAGGAGAGCACACACTTGC-3′(SEQ.ID.NO.:15)

[0935] The primers will amplify a c-H-Ras encoding DNA fragment with theprimers contributing an optimized ‘Kozak’ translation start sequence, anEcoRI site at the N-terminus and a Sal I site at the C-terminal end.After trimming the ends of the PCR product with EcoRI and Sal I, thec-H-ras fragment can be ligated ligated into an EcoRI-Sal I cutmutagenesis vector pAlter-1 (Promega). Mutation of glutamine-61 to aleucine can be accomplished using the manufacturer's protocols and thefollowing oligonucleotide: 5′-CCGCCGGCCTGGAGGAGTACAG-3′ (SEQ.ID.NO.:16)

[0936] After selection and sequencing for the correct nucleotidesubstitution, the mutated c-H-ras-Leu61 can be excised from the pAlter-1vector, using EcoRI and Sal I, and be directly ligated into the vectorpCI (Promega) which has been digested with EcoRI and Sal I. The newrecombinant plasmid, pSMS620, will constitutively transcribec-H-ras-Leu61 from the CMV promoter of the pCI vector.

[0937] Cloning of a c-N-ras-Val-12 expression plasmid pSMS630

[0938] The human c-N-ras gene can be PCRed from a human cerebral cortexcDNA library (Clontech) using the following oligonucleotide primers.Sense strand: 5′-GAGAGAATTCGCCACCATGACTGAGTACAAACTGGTGG-3′(SEQ.ID.NO.:17)

[0939] Antisense strand: 5′-GAGAGTCGACTTGTTACATCACCACACATGGC-3′(SEQ.ID.NO.:18)

[0940] The primers will amplify a c-N-Ras encoding DNA fragment with theprimers contributing an optimized ‘Kozak’ translation start sequence, anEcoRI site at the N-terminus and a Sal I site at the C-terminal end.After trimming the ends of the PCR product with EcoRI and Sal I, thec-N-ras fragment can be ligated into an EcoRI -Sal I cut mutagenesisvector pAlter-l (Promega). Mutation of glycine-12 to a valine can beaccomplished using the manufacturer's protocols and the followingoligonucleotide: 5′-GTTGGAGCAGTTGGTGTTGGG-3′ (SEQ.ID.NO.:19)

[0941] After selection and sequencing for the correct nucleotidesubstitution, the mutated c-N-ras-Val-12 can be excised from thepAlter-1 vector, using EcoRI and Sal I, and be directly ligated into thevector pCI (Promega) which has been digested with EcoRI and Sal I. Thenew recombinant plasmid, pSMS630, will constitutively transcribec-N-ras-Val-12 from the CMV promoter of the pCI vector.

[0942] Cloning of a c-K4B-ras-Val-12 expression plasmid pSMS640

[0943] The human c-K4B-ras gene can be PCRed from a human cerebralcortex cDNA library (Clontech) using the following oligo-nucleotideprimers. Sense strand: 5′-GAGAGGTACCGCCACCATGACTGAATATAAACTTGTGG-3′(SEQ.ID.NO.:20)

[0944] Antisense strand: 5′-CTCTGTCGACGTATTTACATAATTACACACTTTGTC-3′(SEQ.ID.NO.:21)

[0945] The primers will amplify a c-K4B-Ras encoding DNA fragment withthe primers contributing an optimized ‘Kozak’ translation startsequence, a KpnI site at the N-terminus and a Sal I site at theC-terminal end. After trimming the ends of the PCR product with Kpn Iand Sal I, the c-K4B-ras fragment can be ligated into a KpnI -Sal I cutmutagenesis vector pAlter-1 (Promega). Mutation of cysteine-12 to avaline can be accomplished using the manufacturer's protocols and thefollowing oligonucleotide: 5′-GTAGTTGGAGCTGTTGGCGTAGGC-3′(SEQ.ID.NO.:22)

[0946] After selection and sequencing for the correct nucleotidesubstitution, the mutated c-K4B-ras-Val-12 can be excised from thepAlter-1 vector, using KpnI and Sal I, and be directly ligated into thevector pCI (Promega) which has been digested with KpnI and Sal I. Thenew recombinant plasmid will constitutively transcribe c-K4B-ras-Val-12from the CMV promoter of the pCI vector.

[0947] Cloning of c-K-ras4A-Val-12 expression plasmid pSMS650

[0948] The human c-K4A-ras gene can be PCRed from a human cerebralcortex cDNA library (Clontech) using the following oligo-nucleotideprimers. Sense strand: 5′-GAGAGGTACCGCCACCATGACTGAATATAAACTTGTGG-3′(SEQ.ID.NO.:23)

[0949] Antisense strand:5′-CTCTGTCGACAGATTACATTATAATGCATTTTTTAATTTTCACAC-3′ (SEQ.ID.NO.:24)

[0950] The primers will amplify a c-K4A-Ras encoding DNA fragment withthe primers contributing an optimized ‘Kozak’ translation startsequence, a KpnI site at the N-terminus and a Sal I stite at theC-terminal end. After trimming the ends of the PCR product with Kpn Iand Sal I, the c-K-ras4A fragment can be ligated into a KpnI -Sal I cutmutagenesis vector pAlter-1(Promega). Mutation of cysteine-12 to avaline can be accomplished using the manufacturer's protocols and thefollowing oligonucleotide: 5′-GTAGTTGGAGCTGTTGGCGTAGGC-3′(SEQ.ID.NO.:25)

[0951] After selection and sequencing for the correct nucleotidesubstitution, the mutated c-K4A-ras-Val-12 can be excised from thepAlter-1 vector, using KpnI and Sal I, and be directly ligated into thevector pCI (Promega) which has been digested with KpnI and Sal I. Thenew recombinant plasmid, pSMS650, will constitutively transcribec-K4A-ras-Val-12 from the CMV promoter of the pCI vector.

[0952] SEAP assay

[0953] Human C₃₃A cells (human epitheial carcenoma—ATTC collection) areseeded in 10 cm tissue culture plates in DMEM+10% fetal calf serum+1XPen/Strep+1X glutamine+1X NEAA. Cells are grown at 37° C. in a 5% CO₂atmosphere until they reach 50-80% of confluency.

[0954] The transient transfection is performed by the CaPO₄ method(Sambrook et al., 1989). Thus, expression plasmids for H-ras, N-ras,K-ras, Myr-ras or H-ras-CVLL are co-precipitated with the DSE-SEAPreporter construct. (A ras expression plasmid is not included when thecell is transfected with the pCMV-SEAP plasmid.) For 10 cm plates 600 μlof CaCl₂-DNA solution is added dropwise while vortexing to 600 μl of 2×HBS buffer to give 1.2 ml of precipitate solution (see recipes below).This is allowed to sit at room temperature for 20 to 30 minutes. Whilethe precipitate is forming, the media on the C₃₃A cells is replaced withDMEM (minus phenol red; Gibco cat. No. 31053-028)+0.5% charcoal strippedcalf serum+1X (Pen/Strep, Glutamine and nonessential aminoacids). TheCaPO₄-DNA precipitate is added dropwise to the cells and the platerocked gently to distribute. DNA uptake is allowed to proceed for 5-6hrs at 37° C. under a 5% CO₂ atmosphere.

[0955] Following the DNA incubation period, the cells are washed withPBS and trypsinized with 1 ml of 0.05% trypsin. The 1 ml of trypsinizedcells is diluted into 10 ml of phenol red free DMEM+0.2% charcoalstripped calf serum+IX (Pen/Strep, Glutamine and NEAA). Transfectedcells are plated in a 96 well microtiter plate (100 μl/well) to whichdrug, diluted in media, has already been added in a volume of 100 μl.The final volume per well is 200 μl with each drug concentrationrepeated in triplicate over a range of half-log steps.

[0956] Incubation of cells and drugs is for 36 hrs at 37° under CO₂. Atthe end of the incubation period, cells are examined micro-scopicallyfor evidence of cell distress. Next, 100 μl of media containing thesecreted alkaline phosphatase is removed from each well and transferredto a microtube array for heat treatment at 65° C. for 1 hr to inactivateendogenous alkaline phosphatases (but not the heat stable secretedphosphatase).

[0957] The heat treated media is assayed for alkaline phosphatase by aluminescence assay using the luminescence reagent CSPD® (Tropix,Bedford, Mass.). A volume of 50 μl media is combined with 200 μl of CSPDcocktail and incubated for 60 minutes at room temperature. Luminesenceis monitored using an ML2200 microplate luminometer (Dynatech).Luminescence reflects the level of activation of the fos reporterconstruct stimulated by the transiently expressed protein. DNA-CaPO₄precipitate for 10 cm. plate of cells Ras expression plasmid (1 μg/μl)10 μl DSE-SEAP Plasmid (1 μg/μl) 2 μl Sheared Calf Thymus DNA (1 μg/μl)8 μl 2M CaCl₂ 74 μl dH₂O 506 μl 2X HBS Buffer 28O mM NaCl 10 mM KCl 1.5mM Na₂HPO₄2H₂0 12 mM dextrose 50 mM HEPES Final pH = 7.05 LuminesenceBuffer (26 ml) Assay Buffer 20 ml Emerald Reagent ™ (Tropix) 2.5 ml 100mM homoarginine 2.5 ml CSPD Reagent ® (Tropix) 1.0 ml

[0958] Assay Buffer

[0959] Add 0.05M Na₂CO₃ to 0.05M NaHCO₃ to obtain pH 9.5.

[0960] Make 1 mM in MgCl₂

Example 13

[0961] The processing assays employed are modifications of thatdescribed by DeClue et al [Cancer Research 51, 712-717, 1991].

[0962] K4B-Ras processing inhibition assay

[0963] PSN-1(human pancreatic carcinoma) or viral-K4B-ras-transformedRat1 cells are used for analysis of protein processing. Subconfluentcells in 100 mm dishes are fed with 3.5 ml of media (methionine-freeRPMI supplemented with 2% fetal bovine serum orcysteine-free/methionine-free DMEM supplemented with 0.035 ml of 200 mMglutamine (Gibco), 2% fetal bovine serum, respectively) containing thedesired concentration of test compound, lovastatin or solvent alone.Cells treated with lovastatin (5-10 μM), a compound that blocks Rasprocessing in cells by inhibiting a rate-limiting step in the isoprenoidbiosynthetic pathway, serve as a positive control. Test compounds areprepared as 1000× concentrated solutions in DMSO to yield a finalsolvent concentration of 0.1%. Following incubation at 37° C. for twohours 204 μCi/ml [³⁵S]Pro-Mix (Amersham, cell labeling grade) is added.

[0964] After introducing the label amino acid mixture, the cells areincubated at 37° C. for an additional period of time (typically 6 to 24hours). The media is then removed and the cells are washed once withcold PBS. The cells are scraped into 1 ml of cold PBS, collected bycentrifugation (10,000×g for 10 sec at room temperature), and lysed byvortexing in 1 ml of lysis buffer (1% Nonidet P-40, 20 mM HEPES, pH 7.5,150 mM NaCl, 1 mM EDTA, 0.5% deoxycholate, 0.1% SDS, 1 mM DTT, 10 μg/mlAEBSF, 10 μg/ml aprotinin, 2 μg/ml leupeptin and 2 μg/ml antipain). Thelysate is then centrifuged at 15,000×g for 10 min at 4° C. and thesupernatant saved.

[0965] For immunoprecipitation of Ki4B-Ras, samples of lysatesupernatant containing equal amounts of protein are utilized. Proteinconcentration is determined by the bradford method utilizing bovineserum albumin as a standard. The appropriate volume of lysate is broughtto 1 ml with lysis buffer lacking DTT and 8 μg of the pan Ras monoclonalantibody, Y13-259, added. The protein/antibody mixture is incubated onice at 4° C. for 24 hours. The immune complex is collected on pansorbin(Calbiochem) coated with rabbit antiserum to rat IgG (Cappel) bytumbling at 4° C. for 45 minutes. The pellet is washed 3 times with 1 mlof lysis buffer lacking DTT and protease inhibitors and resuspended in100 μl elution buffer (10 mM Tris pH 7.4, 1% SDS). The Ras is elutedfrom the beads by heating at 95° C. for 5 minutes, after which the beadsare pelleted by brief centrifugation (15,000×g for 30 sec. at roomtemperature).

[0966] The supernatant is added to 1 ml of Dilution Buffer 0.1% TritonX-100, 5 mM EDTA, 50 mM NaCl, 10 mM Tris pH 7.4) with 2 μg Kirsten-rasspecific monoclonal antibody, c-K-ras Ab-1 (Calbiochem). The secondprotein/antibody mixture is incubated on ice at 4° C. for 1-2 hours. Theimmune complex is collected on pansorbin (Calbiochem) coated with rabbitantiserum to rat IgG (Cappel) by tumbling at 4° C. for 45 minutes. Thepellet is washed 3 times with 1 ml of lysis buffer lacking DTT andprotease inhibitors and resuspended in Laemmli sample buffer. The Ras iseluted from the beads by heating at 95° C. for 5 minutes, after whichthe beads are pelleted by brief centrifugation. The supernatant issubjected to SDS-PAGE on a 12% acrylamide gel(bis-acrylamide:acrylamide, 1:100), and the Ras visualized byfluorography.

[0967] hDJ processing inhibition assay

[0968] PSN-1 cells are seeded in 24-well assay plates. For each compoundto be tested, the cells are treated with a minimum of sevenconcentrations in half-log steps. The final solvent (DMSO) concentrationis 0.1%. A vehicle-only control is included on each assay plate. Thecells are treated for 24 hours at 37° C./5% CO₂.

[0969] The growth media is then aspirated and the samples are washedwith PBS. The cells are lysed with SDS-PAGE sample buffer containing 5%2-mercaptoethanol and heated to 95° C. for 5 minutes. After cooling onice for 10 minutes, a mixture of nucleases is added to reduce viscosityof the samples.

[0970] The plates are incubated on ice for another 10 minutes. Thesamples are loaded onto pre-cast 8% acrylamide gels and electrophoresedat 15 mA/gel for 3-4 hours. The samples are then transferred from thegels to PVDF membranes by Western blotting.

[0971] The membranes are blocked for at least 1 hour in buffercontaining 2% nonfat dry milk. The membranes are then treated with amonoclonal antibody to hDJ-2 (Neomarkers Cat. # MS-225), washed, andtreated with an alkaline phosphatase-conjugated secondary antibody. Themembranes are then treated with a fluorescent detection reagent andscanned on a phosphorimager.

[0972] For each sample, the percent of total signal corresponding to theunprenylated species of hDJ (the slower-migrating species) is calculatedby densitometry. Dose-response curves and EC₅₀ values are generatedusing 4-parameter curve fits in SigmaPlot software.

Example 14

[0973] Rap1 processing inhibition assay

[0974] Protocol A:

[0975] Cells are labeled, incubated and lysed as described in Example10.

[0976] For immunoprecipitation of Rap I, samples of lysate supernatantcontaining equal amounts of protein are utilized. Protein concentrationis determined by the bradford method utilizing bovine serum albumin as astandard. The appropriate volume of lysate is brought to 1 ml with lysisbuffer lacking DTT and 2 μg of the Rap1 antibody, Rap1/Krev1 (121)(Santa Cruz Biotech), is added. The protein/antibody mixture isincubated on ice at 4° C. for 1 hour. The immune complex is collected onpansorbin (Calbiochem) by tumbling at 4° C. for 45 minutes. The pelletis washed 3 times with 1 ml of lysis buffer lacking DTT and proteaseinhibitors and resuspended in 100 μl elution buffer (10 mM Tris pH 7.4,1% SDS). The Rap1 is eluted from the beads by heating at 95° C. for 5minutes, after which the beads are pelleted by brief centrifugation(15,000×g for 30 sec. at room temperature).

[0977] The supernatant is added to 1 ml of Dilution Buffer (0.1% TritonX-100, 5 mM EDTA, 50 mM NaCl, 10 mM Tris pH 7.4) with 2 μg Rap1antibody, Rap1/Krev1 (121) (Santa Cruz Biotech). The secondprotein/antibody mixture is incubated on ice at 4° C. for 1-2 hours. Theimmune complex is collected on pansorbin (Calbiochem) by tumbling at 4°C. for 45 minutes. The pellet is washed 3 times with 1 ml of lysisbuffer lacking DTT and protease inhibitors and resuspended in Laemmlisample buffer. The Rap1 is eluted from the beads by heating at 95° C.for 5 minutes, after which the beads are pelleted by briefcentrifugation. The supernatant is subjected to SDS-PAGE on a 12%acrylamide gel (bis-acrylamide:acrylamide, 1:100), and the Rap1visualized by fluorography.

[0978] Protocol B:

[0979] PSN-1 cells are passaged every 3-4 days in 10 cm plates,splitting near-confluent plates 1:20 and 1:40. The day before the assayis set up, 5×10⁶ cells are plated on 15 cm plates to ensure the samestage of confluency in each assay. The media for these cells is RPM11640 (Gibco), with 15% fetal bovine serum and 1× Pen/Strep antibioticmix. The day of the assay, cells are collected from the 15 cm plates bytrypsinization and diluted to 400,000 cells/ml in media. 0.5 ml of thesediluted cells are added to each well of 24-well plates, for a final cellnumber of 200,000 per well. The cells are then grown at 37° C.overnight.

[0980] The compounds to be assayed are diluted in DMSO in ½-logdilutions. The range of final concentrations to be assayed is generally0.1-100 μM. Four concentrations per compound is typical. The compoundsare diluted so that each concentration is 1000× of the finalconcentration (i.e., for a 10 μM data point, a 10 mM stock of thecompound is needed).

[0981] 2 μL of each 1000× compound stock is diluted into 1 ml media toproduce a 2X stock of compound. A vehicle control solution (2 ,L DMSO to1 ml media), is utilized. 0.5 ml of the 2X stocks of compound are addedto the cells.

[0982] After 24 hours, the media is aspirated from the assay plates.Each well is rinsed with 1 ml PBS, and the PBS is aspirated. 180 μLSDS-PAGE sample buffer (Novex) containing 5% 2-mercapto-ethanol is addedto each well. The plates are heated to 100° C. for 5 minutes using aheat block containing an adapter for assay plates. The plates are placedon ice. After 10 minutes, 20 μL of an RNAse/DNase mix is added per well.This mix is 1 mg/ml DNaseI (Worthington Enzymes), 0.25 mg/ml Rnase A(Worthington Enzymes), 0.5M Tris-HCl pH 8.0 and 50 mM MgCl₂. The plateis left on ice for 10 minutes. Samples are then either loaded on thegel, or stored at −70° C. until use.

[0983] Each assay plate (usually 3 compounds, each in 4-pointtitrations, plus controls) requires one 15-well 14% Novex gel. 25 μl ofeach sample is loaded onto the gel. The gel is run at 15 mA for about3.5 hours. It is important to run the gel far enough so that there willbe adequate separation between 21 kd (Rap1) and 29 kd (Rab6).

[0984] The gels are then transferred to Novex pre-cut PVDF membranes for1.5 hours at 30V (constant voltage). Immediately after transferring, themembranes are blocked overnight in 20 ml Western blocking buffer (2%nonfat dry milk in Western wash buffer (PBS +0.1% Tween-20). If blockedover the weekend, 0.02% sodium azide is added. The membranes are blockedat 4° C. with slow rocking.

[0985] The blocking solution is discarded and 20ml fresh blockingsolution containing the anti Rap1a antibody (Santa Cruz Biochemical SC1482) at 1:1000 (diluted in Western blocking buffer) and the anti Rab6antibody (Santa Cruz Biochemical SC₃₁₀) at 1:5000 (diluted in Westernblocking buffer) are added. The membranes are incubated at roomtemperature for 1 hour with mild rocking. The blocking solution is thendiscarded and the membrane is washed 3 times with Western wash bufferfor 15 minutes per wash. 20 ml blocking solution containing 1:1000(diluted in Western blocking buffer) each of two alkaline phosphataseconjugated antibodies (Alkaline phosphatase conjugated Anti-goat IgG andAlkaline phosphatase conjugated anti-rabbit IgG [Santa CruzBiochemical]) is then added. The membrane is incubated for one hour andwashed 3× as above.

[0986] About 2 ml per gel of the Amersham ECF detection reagent isplaced on an overhead transparency (ECF) and the PVDF membranes areplaced face-down onto the detection reagent. This is incubated for oneminute, then the membrane is placed onto a fresh transparency sheet.

[0987] The developed transparency sheet is scanned on a phosphorimagerand the Rap1a Minimum Inhibitory Concentration is determined from thelowest concentration of compound that produces a detectable RaplaWestern signal. The Rap1a antibody used recognizes onlyunprenylated/unprocessed Rap1a, so that the precence of a detectableRapla Western signal is indicative of inhibition of Rap1a prenylation.

[0988] Protocol C:

[0989] This protocol allows the determination of an EC₅₀ for inhibitionof processing of Rap1a. The assay is run as described in Protocol B withthe following modifications. 20 μl of sample is run on pre-cast 10-20%gradient acrylamide mini gels (Novex Inc.) at 15 mA/gel for 2.5-3 hours.Prenylated and unprenylated forms of Rap1a are detected by blotting witha polyclonal antibody (Rap1/Krev-1 Ab#121;Santa Cruz Research Products#sc-65), followed by an alkaline phosphatase-conjugated anti-rabbit IgGantibody. The percentage of unprenylated Rap1a relative to the totalamount of Rap1a is determined by peak integration using Imagequant□software (Molecular Dynamics). Unprenylated Rap1a is distinguished fromprenylated protein by virtue of the greater apparent molecular weight ofthe prenylated protein. Dose-response curves and EC₅₀ values aregenerated using 4-parameter curve fits in SigmaPlot software.

Example 15

[0990] In vivo tumor growth inhibition assay (nude mouse)

[0991] In vivo efficacy as an inhibitor of the growth of cancer cellsmay be confirmed by several protocols well known in the art. Examples ofsuch in vivo efficacy studies are described by N. E. Kohl et al. (NatureMedicine, 1:792-797 (1995)) and N. E. Kohl et al. (Proc. Nat. Acad. Sci.U.S.A., 91:9141-9145 (1994)).

[0992] Rodent fibroblasts transformed with oncogenically mutated humanHa-ras or Ki-ras (10⁶ cells/animal in 1 ml of DMEM salts) are injectedsubcutaneously into the left flank of 8-12 week old female nude mice(Harlan) on day 0. The mice in each oncogene group are randomly assignedto a vehicle, compound or combination treatment group. Animals are dosedsubcutaneously starting on day 1 and daily for the duration of theexperiment. Alternatively, the farnesyl-protein transferase inhibitormay be administered by a continuous infusion pump. Compound, compoundcombination or vehicle is delivered in a total volume of 0.1 ml. Tumorsare excised and weighed when all of the vehicle-treated animalsexhibited lesions of 0.5-1.0 cm in diameter, typically 11-15 days afterthe cells were injected. The average weight of the tumors in eachtreatment group for each cell line is calculated.

1 25 1 4 PRT Artificial Sequence N-terminus of Ras protein 1 Cys Val LeuLeu 1 2 4 PRT Artificial Sequence N-terminus of Ras protein 2 Cys ValLeu Ser 1 3 15 PRT Artificial Sequence Completely Synthetic Amino Acid 3Gly Lys Lys Lys Lys Lys Lys Ser Lys Thr Lys Cys Val Ile Met 1 5 10 15 452 DNA Artificial Sequence Artificial Nucleotide Sequence 4 gagagggaattcgggccctt cctgcatgct gctgctgctg ctgctgctgg gc 52 5 41 DNA ArtificialSequence Artificial Antisense Nucleotide Sequence 5 gagagagctcgaggttaacc cgggtgcgcg gcgtcggtgg t 41 6 42 DNA Artificial SequenceArtificial Nucleotide Sequence 6 gagagagtct agagttaacc cgtggtccccgcgttgcttc ct 42 7 43 DNA Artificial Sequence Artificial AntisenseNucleotide Sequence 7 gaagaggaag cttggtaccg ccactgggct gtaggtggtg gct 438 27 DNA Artificial Sequence Artificial Nucleotide Sequence 8 ggcagagctcgtttagtgaa ccgtcag 27 9 27 DNA Artificial Sequence Artificial AntisenseNucleotide Sequence 9 gagagatctc aaggacggtg actgcag 27 10 86 DNAArtificial Sequence Artificial Nucleotide Sequence 10 tctcctcgaggccaccatgg ggagtagcaa gagcaagcct aaggacccca gccagcgccg 60 gatgacagaatacaagcttg tggtgg 86 11 33 DNA Artificial Sequence Artificial AntisenseNucleotide Sequence 11 cacatctaga tcaggacagc acagacttgc agc 33 12 41 DNAArtificial Sequence Artificial Nucleotide Sequence 12 tctcctcgaggccaccatga cagaatacaa gcttgtggtg g 41 13 38 DNA Artificial SequenceArtificial Antisense Nucleotide Sequence 13 cactctagac tggtgtcagagcagcacaca cttgcagc 38 14 38 DNA Artificial Sequence ArtificialNucleotide Sequence 14 gagagaattc gccaccatga cggaatataa gctggtgg 38 1533 DNA Artificial Sequence ArtificialAntisense Nucleotide Sequence 15gagagtcgac gcgtcaggag agcacacact tgc 33 16 22 DNA Artificial SequenceArtificial Nucleotide Sequence 16 ccgccggcct ggaggagtac ag 22 17 38 DNAArtificial Sequence Artificial Nucleotide Sequence 17 gagagaattcgccaccatga ctgagtacaa actggtgg 38 18 32 DNA Artificial SequenceArtificial Antisense Nucleotide Sequence 18 gagagtcgac ttgttacatcaccacacatg gc 32 19 21 DNA Artificial Sequence Artificial NucleotideSequence 19 gttggagcag ttggtgttgg g 21 20 38 DNA Artificial SequenceArtificial Antisense Nucleotide Sequence 20 gagaggtacc gccaccatgactgaatataa acttgtgg 38 21 36 DNA Artificial Sequence ArtificialNucleotide Sequence 21 ctctgtcgac gtatttacat aattacacac tttgtc 36 22 24DNA Artificial Sequence Artificial Nucleotide Sequence 22 gtagttggagctgttggcgt aggc 24 23 38 DNA Artificial Sequence Artificial NucleotideSequence 23 gagaggtacc gccaccatga ctgaatataa acttgtgg 38 24 45 DNAArtificial Sequence Artificial Antisense Nucleotide Sequence 24ctctgtcgac agattacatt ataatgcatt ttttaatttt cacac 45 25 24 DNAArtificial Sequence Artificial Nucleotide Sequence 25 gtagttggagctgttggcgt aggc 24

What is claimed is:
 1. A compound of the formula A:

wherein: R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are independentlyselected from: a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃-C₁₀ cycloalkyl, C₁-C₆perfluoroalkyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN,NO₂, (R¹⁰)₂N—C(NR¹⁰)—, (R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂,or R¹¹OC(O)NR O—, c) unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl or unsubstituted orsubstituted C₂-C₆ alkynyl, wherein the substituent on the substituted Ci-C₆ alkyl, substituted C₂-C₆ alkenyl or substituted C₂-C₆ alkynyl isselected from unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, halogen,R¹⁰O—, R⁴S(O)_(m)—, R⁴S(O)₂NR¹⁰—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; ortwo R^(1a)s, two R^(1b)s, two R^(1c)s or two R^(1e)s, on the same carbonatom may be combined to form —(CH₂)_(v)—, wherein one of the CH₂moieties is optionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴ isselected from C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, e)

f) —SO₂R¹¹, g) N(R¹⁰)₂, or h) C₁₋₄ perfluoroalkyl; R⁶ and R⁷ areindependently selected from: 1) hydrogen, 2) R¹⁰C(O)—, or R¹⁰OC(O)—, and3) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃₋₆ cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with one or more substituents selectedfrom: a) R¹⁰O—, b) aryl or heterocycle, c) halogen, d) R¹⁰C(O)NR¹⁰—, e)

f) —SO₂R¹¹, g) N(R¹⁰)₂, h) C₃₋₆ cycloalkyl, i) C₁-C₆ perfluoroalkyl, j)(R¹⁰)₂N—C(NR¹⁰)—, k) R¹⁰OC(O)—, l) R¹¹OC(O)NR¹⁰—, m) CN, and n) NO₂, orR⁶ and R⁷ may be joined in a ring; R⁸ is independently selected from: a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹²O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl unsubstitutedor substituted by unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—,R¹⁰C(O)NH—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, R¹⁰OC(O)—,—N(R¹⁰)₂, or R¹⁰OC(O)NH—; R⁹ is selected from: a) hydrogen, b) C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹⁰O—,R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkylunsubstituted or substituted by C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹⁰O—,R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R¹⁰ is independently selectedfrom hydrogen, C₁-C₆ alkyl, unsubstituted or substituted benzyl,unsubstituted or substituted aryl and unsubstituted or substitutedheterocycle; R¹¹ is independently selected from C₁-C₆ alkylunsubstituted or substituted aryl and unsubstituted or substitutedheterocycle; R¹² is independently selected from hydrogen, C₁-C₆ alkyl,C₁-C₃ perfluoroalkyl, unsubstituted or substituted benzyl, unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, and C₁-C₆alkyl substituted with unsubstituted or substituted aryl orunsubstituted or substituted heterocycle; A¹ is selected from a bond,—C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,—N(R¹⁰)S(O)₂—, and S(O)_(m); A² is selected from a bond, —C(O)—,—C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—,—NR¹⁰C(O)NR¹⁰—, S(O)_(m) and —C(R¹c)₂—; W is heteroaryl; V is selectedfrom: a) heteroaryl, and b) aryl; X is selected from —C(O)—, —C(O)NR¹⁰—,—NR¹⁰C(O)—, —NR¹⁰C(O)—O—, —O—C(O)NR¹⁰—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂— and S(O)_(m); Z¹ is selected fromunsubstituted or substituted aryl and unsubstituted or substitutedheterocycle, wherein the substituted aryl or substituted heterocycle issubstituted with one or more of: 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈alkynyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, g)—C(O)NR⁶R⁷, or h) C₁₄ perfluoroalkyl; 2) substituted or unsubstitutedaryl or substituted or unsubstituted heterocycle, 3) halogen, 4) OR⁶, 5)NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —OS(O)₂R⁴, 11)—C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆ cycloalkyl; provided that Z¹ isnot selected from piperazinyl, oxopiperazinyl, dioxopiperazinyl,piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² is selected from a bond,unsubstituted or substituted aryl and unsubstituted or substitutedheteroaryl, wherein the substituted aryl or substituted heteroaryl issubstituted with one or more of: 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈alkynyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, g)—C(O)NR⁶R⁷, or h) C₁₋₄perfluoroalkyl; 2) substituted or unsubstitutedaryl or substituted or unsubstituted heterocycle, 3) halogen, 4) OR⁶, 5)NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —OS(O)₂R⁴, 11)—C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆ cycloalkyl; provided that Z² isnot selected from piperazinyl, oxopiperazinyl, dioxopiperazinyl,piperidinyl, oxopiperidinyl or pyrrolidinyl; m is 0, 1 or 2; n is 0, 1,2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to 5; s isindependently 0, 1, 2 or 3; t is 1, 2, 3, 4, 5, 6 or 7; and v is 2 to 6;or a pharmaceutically acceptable salt or stereoisomer thereof.
 2. Thecompound according to claim 1 which is:

wherein: R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) are independentlyselected from: a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl,R¹⁰O—, R¹¹ S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, NO₂,(R¹⁰)₂N—C(NR¹⁰)—, (R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—, c) unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl or unsubstituted orsubstituted C₂-C₆ alkynyl, wherein the substituent on the substitutedC₁-C₆ alkyl, substituted C₂-C₆ alkenyl or substituted C₂-C₆ alkynyl isselected from unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰O—, R¹¹S(O)_(m)—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—,—N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; or two R^(1e)s, on the same carbon atommay be combined to form —(CH₂)_(v)— wherein one of the CH₂ moieties isoptionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected fromC₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d)HO, e)

f) —SO₂R¹¹, or g) N(R¹⁰)₂; R⁶ and R⁷ are independently selected from H;C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl,arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a)C₁₋₄ alkoxy, b) aryl or heterocycle, c) halogen, d) HO, e)

f) —SO₂R¹¹, or g) N(R¹⁰)₂, or R⁶ and R⁷ may be joined in a ring; R⁸ isindependently selected from: a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl,Br, R¹²O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—,CN, NO₂, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆alkyl unsubstituted or substituted by unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰O—, R¹¹S(O)_(m)—,R¹⁰C(O)NH—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, R¹⁰C(O)—, R¹⁰OC(O)—,—N(R¹⁰)₂, or R¹⁰OC(O)NH—; R⁹ is selected from: a) hydrogen, b) C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹⁰O—,R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, CN, NO₂,R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkylunsubstituted or substituted by C₁-C₆ perfluoroalkyl, F, Cl, Br, R¹⁰O—,R¹¹S(O)_(m)—, CN, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂NC(O)—, R¹⁰ ₂N—C(NR¹⁰)—, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂ or R¹¹OC(O)NR¹⁰—; R¹⁰ is independently selected fromhydrogen, C₁-C₆ alkyl, benzyl, unsubstituted or substituted aryl andunsubstituted or substituted heterocycle; R¹¹ is independently selectedfrom C₁-C₆ alkyl unsubstituted or substituted aryl and unsubstituted orsubstituted heterocycle; R¹² is independently selected from hydrogen,C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl, unsubstituted or substituted benzyl,unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, and C₁-C₆ alkyl substituted with unsubstituted orsubstituted aryl or unsubstituted or substituted heterocycle; A¹ isselected from a bond, —N(R¹⁰)—, S(O)_(m) and O; A² is selected from abond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,—N(R¹¹)S(O)₂—, —NR1 OC(O)NR¹⁰—, S(O)_(m) and —C(R^(1c))₂—; W isheteroaryl; V is selected from: a) heteroaryl, and b) aryl; X isselected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)—O—,—O—C(O)NR¹⁰—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—and S(O)_(m); Z¹ is selected from unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of: 1) C₁₋₄alkyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, or g)—C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN,7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl;provided that Z¹ is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² isselected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of: 1) C₁₋₄alkyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, or g)—C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN,7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl;provided that Z² is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; m is 0, 1or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 1 or 2; r is 0 to5; s is independently 0, 1, 2 or 3; and t is 1, 2, 3, 4, 5, 6 or 7; or apharmaceutically acceptable salt or stereoisomer thereof.
 3. Thecompound according to claim 2 which is:

wherein: R^(1a), R^(1b) and R^(1c) are independently selected fromhydrogen and C₁-C₆ alkyl; R^(1d) and R^(1e) are independently selectedfrom: a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O— or—N(R¹⁰)₂, and c) unsubstituted or substituted C₁-C₆ alkyl, unsubstitutedor substituted C₂-C₆ alkenyl or unsubstituted or substituted C₂-C₆alkynyl, wherein the substituent on the substituted C₁-C₆ alkyl,substituted C₂-C₆ alkenyl or substituted C₂-C₆ alkynyl is selected from:unsubstituted or substituted aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆alkenyl, R¹⁰O— and —N(R¹⁰)₂; or two R^(1e)s, on the same carbon atom maybe combined to form —(CH₂)_(v)—, wherein one of the CH₂ moieties isoptionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected fromC₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with: a)C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle; R⁶ and R⁷ areindependently selected from H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, aryl andheterocycle, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b)halogen, or c) aryl or heterocycle; R⁸ is independently selected from:a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN, NO₂,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆alkyl substituted by: unsubstituted or substituted aryl, unsubstitutedor substituted heterocycle, C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R⁹ is selectedfrom: a) hydrogen, b) C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perfluoroalkyl, F, Cl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, NO₂,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆alkyl unsubstituted or substituted by C₁-C₆ perfluoroalkyl, F, Cl,R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—, CN, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,—N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R¹⁰ is independently selected from hydrogen,C₁-C₆ alkyl, benzyl, unsubstituted or substituted aryl and unsubstitutedor substituted heterocycle; R¹¹ is independently selected from C₁-C₆alkyl, unsubstituted or substituted aryl and unsubstituted orsubstituted heterocycle; R¹² is independently selected from hydrogen,C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl, unsubstituted or substituted benzyl,unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, and C₁-C₆ alkyl substituted with unsubstituted orsubstituted aryl or unsubstituted or substituted heterocycle; A¹ isselected from a bond, —N(R¹⁰)—, S(O)_(m) and O; A² is selected from abond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,—N(R¹⁰)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—; V is selected from: a)heterocycle selected from pyridinyl, pyridonyl, 2-oxopiperidinyl,indolyl, quinolinyl and isoquinolinyl, and b) aryl; W is a heterocycleselected from imidazolyl, pyridinyl, and triazolyl; X and Y areindependently selected from —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,—NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m);Z¹ is selected from unsubstituted or substituted aryl or unsubstitutedor substituted heteroaryl, wherein the substituted aryl or substitutedheteroaryl is independently substituted with one or two of: 1) C₁₋₄alkyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, or g)—C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN,7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl;provided that Z¹ is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² isselected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted independently with one or twoof: 1) C₁₋₄ alkyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b)NR⁶R⁷, c) C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f)—S(O)_(m)R⁴, or g) —C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4)OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or11) C₃-C₆ cycloalkyl; provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or4; q is 1 or 2; r is 0 to 5; s is independently 0, 1, 2 or 3; and t is1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt orstereoisomer thereof
 4. The compound according to claim 1 of the formulaB:

wherein: R^(1a), R^(1b) and R^(1c) are independently selected from: a)hydrogen, b) aryl, heterocycle, cycloalkyl, R¹⁰O—, —N(R¹⁰)₂ or C₂-C₆alkenyl, and c) C₁-C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂;R^(1d) and R^(1e) are independently selected from: a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O—, R¹¹S(O)_(m)—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(O)—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—, (R¹⁰)₂N—C(O)NR¹⁰—, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, c) unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl or unsubstitutedor substituted C₂-C₆ alkynyl, wherein the substituent on the substitutedC₁-C₆ alkyl, substituted C₂-C₆ alkenyl or substituted C₂-C₆ alkynyl isselected from: unsubstituted or substituted aryl, heterocyclic, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, halogen,R¹⁰O—, R⁴S(O)_(m)—, R⁴S(O)₂NR¹⁰—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(O)—, CN,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, and R¹¹OC(O)—NR¹⁰—; ortwo R^(1e)s, on the same carbon atom may be combined to form—(CH₂)_(v)—, wherein one of the CH₂ moieties is optionally replaced with—C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected from C₁₋₄ alkyl and C₃₋₆cycloalkyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b)halogen, or c) aryl or heterocycle; R⁶ and R⁷ are independently selectedfrom H; C₁₋₆ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl, aroyl,heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with one or two: a) C₁₋₄ alkoxy, b) aryl or heterocycle, c)halogen, d) HO, e)

f) —SO₂R¹¹, g) N(R¹⁰)₂, or h) C₃₋₆ cycloalkyl; R⁸ is independentlyselected from: a) hydrogen, b) unsubstituted or substituted aryl, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²O—,R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl substituted by: unsubstituted orsubstituted aryl, C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R^(9a) isselected from hydrogen, C₁-C₆ alkyl and C₁-C₆ perfluoroalkyl; R¹⁰ isindependently selected from hydrogen, C₁-C₆ alkyl, benzyl andunsubstituted or substituted aryl; R¹¹ is independently selected fromC₁-C₆ alkyl and unsubstituted or substituted aryl; R¹² is independentlyselected from hydrogen, C₁-C₆ alkyl, unsubstituted or substitutedbenzyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, and C₁-C₆ alkyl substituted with unsubstituted orsubstituted aryl or unsubstituted or substituted heterocycle; A¹ isselected from a bond, —N(R¹⁰)—, S(O)_(m) and O; A² is selected from abond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—,—N(R¹I)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—; V is selected from: a)heterocycle selected from pyridinyl, pyridonyl, 2-oxopiperidinyl,indolyl, quinolinyl and isoquinolinyl, and b) aryl; X is selected from—C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹¹)S(O)₂—, and S(O)_(m); Z¹ is selected fromunsubstituted or substituted aryl or unsubstituted or substitutedheterocycle, wherein the substituted aryl or substituted heterocycle isindependently substituted with one or two of: 1) C₁₋₈ alkyl, C₂₋₈alkenyl or C₂₋₈ alkynyl, unsubstituted or substituted with: a) C₁₋₄alkoxy, b) NR⁶R⁷, c) C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f)—S(O)_(m)R⁴, g) —C(O)NR⁶R⁷, or h) C₁₋₄ perfluoroalkyl; 2) substituted orunsubstituted aryl or substituted or unsubstituted heterocycle, 3)halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10)—OS(O)₂R⁴, 11) —C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆ cycloalkyl;provided that Z¹ is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² isselected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of: 1) C₁₋₈alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) NR⁶R⁷ c) C₃₋₆ cycloalkyl, d) aryl or heterocycle, e)HO, f) —S(O)_(m)R⁴, g) —C(O)NR⁶R⁷, or h) C₁₋₄ perfluoroalkyl; 2)substituted or unsubstituted aryl or substituted or unsubstitutedheterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷. 6) CN, 7) NO₂, 8) CF₃, 9)—S(O)_(m)R⁴, 10) —OS(O)₂R⁴, 11) —C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆cycloalkyl; provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or4; r is 0 to 5; s is 0, 1, 2 or 3; and t is 1, 2, 3, 4, 5, 6 or 7; or apharmaceutically acceptable salt or stereoisomer thereof.
 5. Thecompound according to claim 1 of the formula B:

wherein: R^(1a), R^(1b) and R^(1c) are independently selected fromhydrogen or C₁-C₆ alkyl; R^(1d) and R^(1e) are independently selectedfrom: a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cyloalkyl, R¹⁰O— or—N(R¹⁰)₂, and c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl,unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂; or two R^(1e)s on the same carbonatom may be combined to form —(CH₂)_(v)—, wherein one of the CH₂moieties is optionally replaced with —C(O)—, —NH— or —NHC(═O)—; R⁴ isselected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle;R⁶ and R⁷ are independently selected from: a) hydrogen, b) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— or R¹⁰OC(O)— and c) C₁-C₆ alkylsubstituted by C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R⁸ isindependently selected from: a) hydrogen, b) unsubstituted orsubstituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perfluoroalkyl, F, Cl, R¹²O—, R¹OC(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl substituted by:unsubstituted or substituted aryl, C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆ perfluoroalkyl;R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl andunsubstituted or substituted aryl; R¹¹ is independently selected fromC₁-C₆ alkyl and unsubstituted or substituted aryl; R¹² is independentlyselected from hydrogen, C₁-C₆ alkyl, unsubstituted or substitutedbenzyl, unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, and C₁-C₆ alkyl substituted with unsubstituted orsubstituted aryl or unsubstituted or substituted heterocycle; A¹ isselected from a bond, —N(R¹⁰)—, S(O)_(m) and O; A² is selected from abond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—, —S(O)₂N(RIO)—,—N(R¹I)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—; V is selected from: a)heteroaryl selected from imidazolyl, pyridinyl, thiazolyl, indolyl,quinolinyl, isoquinolinyl, and thienyl, and b) aryl; X is selected from—C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m); Z¹ is selected fromunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl, wherein the substituted aryl or substituted heteroaryl isindependently substituted with one or two of: 1) C₁₋₄ alkyl,unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c) C₃₋₆cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, or g)—C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN,7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl;provided that Z¹ is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² isselected from a bond, unsubstituted or substituted aryl andunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or more of: 1) C₁₋₈alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) NR⁶R⁷, c) C₃₋₆ cycloalkyl, d) aryl or heterocycle, e)HO, f) —S(O)_(m)R⁴, g) —C(O)NR⁶R⁷, or h) C₁₋₄ perfluoroalkyl; 2)substituted or unsubstituted aryl or substituted or unsubstitutedheterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9)—S(O)_(m)R⁴, 10) —OS(O)₂R⁴, 11) —C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆cycloalkyl; provided that Z² is not selected from piperazinyl,oxopiperazinyl, dioxopiperazinyl, piperidinyl, oxopiperidinyl orpyrrolidinyl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or4; r is 0 to 5; s is independently 0, 1, 2 or 3; and t is 1, 2, 3, 4, 5,6 or 7; or a pharmaceutically acceptable salt or stereoisomer thereof.6. The compound according to claim 4 of the formula C:

wherein: g is CH or N; R^(1a), R^(1b) and R^(1c) are independentlyselected from hydrogen or C₁-C₆ alkyl; R^(1d) and R^(1e) areindependently selected from: a) hydrogen, b) aryl, heterocycle, C₃-C₁₀cycloalkyl, R¹⁰O— or —N(R¹⁰)₂, and c) C₁-C₆ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl, unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂; or two R^(1e)s on thesame carbon atom may be combined to form —(CH₂)_(v)—, wherein one of theCH₂ moieties is optionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle;R⁶ and R⁷ are independently selected from: a) hydrogen, b) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— or R¹⁰OC(O)— and c) C₁-C₆ alkylsubstituted by C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O), R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R⁸ isindependently selected from: a) hydrogen, b) unsubstituted orsubstituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl substituted byunsubstituted or substituted aryl, C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆ perfluoroalkyl;R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, benzyl andunsubstituted or substituted aryl; R¹¹ is independently selected fromC₁-C₆ alkyl and unsubstituted or substituted aryl; R¹² is independentlyselected from hydrogen, C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl, unsubstitutedor substituted benzyl, unsubstituted or substituted aryl, unsubstitutedor substituted heterocycle, and C₁-C₆ alkyl substituted withunsubstituted or substituted aryl or unsubstituted or substitutedheterocycle; A¹ is selected from a bond, —N(R¹⁰)—, S(O)_(m) and O; A² isselected from a bond, —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, O, —N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, S(O)_(m) and —C(R^(1c))₂—; X is selectedfrom: —C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m); Z¹ is selected fromunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl, wherein the substituted aryl or substituted heteroaryl issubstituted with one or two of: 1) C₁₋₄ alkyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c) C₃₋₆ cycloalkyl, d) arylor heterocycle, e) HO, f) —S(O)_(m)R⁴, or g) —C(O)NR⁶R⁷, 2) aryl orheterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9)—S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl; provided that Z¹is not selected from piperazinyl, oxopiperazinyl, dioxopiperazinyl,piperidinyl, oxopiperidinyl or pyrrolidinyl; Z² is selected from a bond,unsubstituted or substituted aryl and unsubstituted or substitutedheteroaryl, wherein the substituted aryl or substituted heteroaryl issubstituted with one or more of: 1) C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈alkynyl, unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c)C₃₋₆ cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, g)—C(O)NR⁶R⁷, or h) C₁₋₄ perfluoroalkyl; 2) substituted or unsubstitutedaryl or substituted or unsubstituted heterocycle, 3) halogen, 4) OR⁶, 5)NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —OS(O)₂R⁴, 11)—C(O)NR⁶R⁷, 12) —C(O)OR⁶, or 13) C₃-C₆ cycloalkyl; provided that Z² isnot selected from piperazinyl, oxopiperazinyl, dioxopiperazinyl,piperidinyl, oxopiperidinyl or pyrrolidinyl; m is 0, 1 or 2; n is 0, 1,2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5; s is independently 0, 1, 2or 3; and t is 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptablesalt or stereoisomer thereof.
 7. The compound according to claim 6 ofthe formula D:

wherein: R^(1b) and R^(1c) are independently selected from hydrogen orC₁-C₆ alkyl; R^(1d) and R^(1e) are independently selected from: a)hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰O— or —N(R¹⁰), andc) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, unsubstituted orsubstituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl,R¹⁰O—, or —N(R¹⁰)₂; or two R^(1e)s on the same carbon atom may becombined to form —(CH₂)_(v)—, wherein one of the CH₂ moieties isoptionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴ is selected fromC₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted or substituted with: a)C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle; R⁶ and R⁷ areindependently selected from: a) hydrogen, b) C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, R¹⁰C(O)— or R¹⁰OC(O)— and c) C₁-C₆ alkyl substituted byC₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—,R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R⁸ is independently selectedfrom: a) hydrogen, b) unsubstituted or substituted aryl, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹²0—,R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, orR¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl substituted by unsubstituted orsubstituted aryl, C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹C(O)NR¹⁰—; R^(9a) isselected from hydrogen, C₁-C₆ alkyl and C₁-C₆ perfluoroalkyl; R¹⁰ andR¹² are independently selected from hydrogen, C₁-C₆ alkyl, benzyl andunsubstituted or substituted aryl; R¹¹ is independently selected fromC₁-C₆ alkyl and unsubstituted or substituted aryl; A¹ is selected from abond, —N(R¹⁰)—, S(O)_(m) and O; X is selected from: —C(O)—, —C(O)NR¹⁰—,—NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—, —S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—,and S(O)_(m); Z¹ is selected from unsubstituted or substituted aryl orunsubstituted or substituted heteroaryl, wherein the substituted aryl orsubstituted heteroaryl is substituted with one or two of: 1) C₁₋₄ alkyl,unsubstituted or substituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c) C₃₋₆cycloalkyl, d) aryl or heterocycle, e) HO, f) —S(O)_(m)R⁴, or g)—C(O)NR⁶R⁷, 2) aryl or heterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN,7) NO₂, 8) CF₃, 9) —S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl;provided that Z¹ is not selected from piperazinyl, oxopiperazinyl,dioxopiperazinyl, piperidinyl, oxopiperidinyl or pyrrolidinyl; m is 0, 1or 2; n is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0 to 5; s isindependently 0, 1, 2 or 3; and t is 1, 2, 3, 4, 5, 6 or 7; or apharmaceutically acceptable salt or stereoisomer thereof.
 8. Thecompound according to claim 6 of the formula E:

wherein: R^(1b) and R^(1c) are independently selected from hydrogen orC₁-C₆ alkyl; R^(1d) is selected from: a) hydrogen, b) aryl, heterocycleor C₃-C₁₀ cycloalkyl, and c) C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl, unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂; R^(1e) is independentlyselected from: a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl,R¹⁰O—, —N(R¹⁰)₂ or C₂-C₆ alkenyl, and c) C₁-C₆ alkyl, C₂-C₆ alkenyl orC₂-C₆ alkynyl, unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀cycloalkyl, C₂-C₆ alkenyl, R¹⁰O—, or —N(R¹⁰)₂; or two R^(1e)s on thesame carbon atom may be combined to form —(CH₂)_(v)—, wherein one of theCH₂ moieties is optionally replaced with —C(═O)—, —NH— or —NHC(═O)—; R⁴is selected from C₁₋₄ alkyl and C₃₋₆ cycloalkyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) halogen, or c) aryl or heterocycle;R⁶ and R⁷ are independently selected from: a) hydrogen, b) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰C(O)— or R¹⁰OC(O)— and c) C₁-C₆ alkylsubstituted by C₁-C₆ perfluoroalkyl, R¹⁰O—, R¹⁰C(O)NR¹⁰—,(R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, R¹⁰OC(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—; R⁸ isindependently selected from: a) hydrogen, b) unsubstituted orsubstituted aryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆perfluoroalkyl, F, Cl, R¹²O—, R¹⁰C(O)NR¹⁰—, CN, NO₂, (R¹⁰)₂N—C(NR¹⁰)—,R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—, and c) C₁-C₆ alkyl substituted byunsubstituted or substituted aryl, C₁-C₆ perfluoroalkyl, R¹⁰O—,R¹⁰C(O)NR¹⁰—, (R¹⁰)₂N—C(NR¹⁰)—, R¹⁰C(O)—, —N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰—;R^(9a) is selected from hydrogen, C₁-C₆ alkyl and C₁-C₆ perfluoroalkyl;R¹⁰ and R¹² are independently selected from hydrogen, C₁-C₆ alkyl,benzyl and unsubstituted or substituted aryl; R¹¹ is independentlyselected from C₁-C₆ alkyl and unsubstituted or substituted aryl; A¹ isselected from a bond, —N(R¹⁰)—, S(O)_(m) and O; X is selected from—C(O)—, —C(O)NR¹⁰—, —NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, and S(O)_(m); Z¹ is selected fromunsubstituted or substituted aryl or unsubstituted or substitutedheteroaryl, wherein the substituted aryl or substituted heteroaryl issubstituted with one or two of: 1) C₁₋₄ alkyl, unsubstituted orsubstituted with: a) C₁₋₄ alkoxy, b) NR⁶R⁷, c) C₃₋₆ cycloalkyl, d) arylor heterocycle, e) HO, f) —S(O)_(m)R⁴, or g) —C(O)NR⁶R⁷, 2) aryl orheterocycle, 3) halogen, 4) OR⁶, 5) NR⁶R⁷, 6) CN, 7) NO₂, 8) CF₃, 9)—S(O)_(m)R⁴, 10) —C(O)NR⁶R⁷, or 11) C₃-C₆ cycloalkyl; provided that Z¹is not selected from piperazinyl, oxopiperazinyl, dioxopiperazinyl,piperidinyl, oxopiperidinyl or pyrrolidinyl; m is 0, 1 or 2; n is 0, 1,2, 3 or 4; p is 0, 1, 2, 3 or 4; provided p is 1, 2, 3 or 4 when X is—NR¹⁰C(O)—, —NR¹⁰C(O)NR¹⁰—, O, —N(R¹⁰)— or N(R¹⁰)S(O)₂—; r is 0 to 5; sis independently 0, 1, 2 or 3; and t is 1, 2, 3, 4, 5, 6 or 7; or apharmaceutically acceptable salt or stereoisomer thereof.
 9. A compoundwhich is selected from:5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[11.3.1.1^(3,7)]octadeca-1(16),3(18),4,6,13(17),14-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3(20),4,6,15(19),16-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate; 5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-l1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;5-(4-Cyano-8-methyl-10-oxo-2-oxa-9-aza-(16-spiro-(2-cyclohexanone)tricyclo[15.3.1.1^(3,7)]docosa-1(20),3(22),4,6,17(21),18-hexaen-8-yl)-1-methyl-1H-imidazol-1-ium2,2,2-trifluoroacetate;14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile;15-Amino-15-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[14.3.1.1^(3,7)]heneicosa-1(20),3,5,7(21),16.18-hexaene-19-carbonitrile;14-amino-14-(3-methyl-3H-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrileor a free base, a pharmaceutically acceptable salt or stereoisomersthereof.
 10. The compound according to claim 9 which is14-Amino-14-(3-methyl-3H-imidazol-4-yl)-2,9-dioxa-tricyclo[13.3.1.1^(3,7)]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile;

or a pharmaceutically acceptable salt or stereoisomer thereof.
 11. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 1. 12. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 6. 13. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 9. 14. A method for inhibitingprenyl protein transferase which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 1. 15. A method for inhibiting prenyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 12. 16. A method forinhibiting prenyl-protein transferase which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 13. 17. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 11. 18. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 12. 19. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 13. 20. A method for treating neurofibromin benign proliferativedisorder which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 11. 21. Amethod for treating blindness related to retinal vascularization whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 11. 22. A method for treatinginfections from hepatitis delta and related viruses which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 11. 23. A method for preventingrestenosis which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 11. 24. Amethod for treating polycystic kidney disease which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 11. 25. A method of conferringradiation sensitivity on a tumor cell using a therapeutically effectiveamount of a composition of claim 11 in combination with radiationtherapy.
 26. A method of using a therapeutically effective amount of acomposition of claim 11 in combination with an antineoplastic to treatcancer.
 27. A method according to claim 26 wherein the antineoplastic ispaclitaxel.
 28. A pharmaceutical composition made by combining thecompound of claim 1 and a pharmaceutically acceptable carrier.
 29. Aprocess for making a pharmaceutical composition comprising combining acompound of claim 1 and a pharmaceutically acceptable carrier.